Clinical trial NCT02443337
Conditions: Non-small Cell Lung Cancer Metastatic
Sponsor: Eli Lilly and Company
Start date: 2015-07-01; Completion date: 2017-09-01
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the safety and activity of the study drug known as LY3023414 in combination with necitumumab in participants with metastatic squamous non-small cell lung cancer (NSCLC).

Detailed description:

Arms: arm 1: 200 milligrams (mg) LY3023414 administered orally twice daily and 800 mg necitumumab administered intravenously (IV) on day 1 and day 8 of each cycle (21 day cycles). Participants may continue to receive treatment until discontinuation criteria are met.
Interventions: intervention 1: LY3023414 intervention 2: Necitumumab
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol I6A-MC-CBBE (b) 
A Phase II Study of the Combination of LY3023414 and Necitumumab after First-Line 
Chemotherapy for Metastatic Squamous Non-small Cell Carcinoma of the Lung 
 
NCT02443337  
 
Approval Date: 16 December 2015 
 


 
 
CONFIDENTIAL 
STUDY DRUG(S): LY3023414 
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE 
AMENDMENT 2:  23 November 2015  
 
 
 
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Approval Date: 16-Dec-2015 GMT 
LUN 288/I6A-MC-CBBE 
A Phase II Study of the Combination of LY3023414 and Necitumumab after First-Line 
Chemotherapy for Metastatic Squamous Non-small Cell Carcinoma of the Lung 
SCRI DEVELOPMENT INNOVATIONS, LLC 
(SCRI INNOVATIONS) STUDY NUMBER: 
LUN 288 
SPONSOR STUDY NUMBER: 
I6A-MC-CBBE 
STUDY DRUG: 
LY3023414 
SPONSOR: 
Eli Lilly and Company 
Indianapolis, Indiana, 46285  USA   
CONTRACT RESEARCH ORGANIZATION: 
SCRI Innovations 
3322 West End Avenue , Suite 900 
Nashville, TN  37203 
 
 
STUDY CHAIR: 
 MD 
Sarah Cannon Research Institute 
3322 West End Avenue , Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI  
SPONSOR CONTACT : 
 MD, PhD 
Eli Lilly and Company 
Kolblgasse 8-10 
A-1030 Vienna, Austria 
 
DATE FINAL: 
27 February 2015 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:  
08 April 2015 
AMENDMENT NUMBER: 
2 
AMENDMENT DATE:  
23 November 2015 
Protocol Approved by Lilly:  04 March 2015 
Amendment (a) Electronically Signed and Approved by Lilly on date provided below. 
 
 
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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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Clinical Study Statement of Compliance
A Phase II Study of the Combination of LY3023414 and Necitumumab after 
First-Line Chemotherapy for Metastatic Squamous Non-small Cell 
Carcinoma of the Lung
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to:

International Conference on Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP)

Ethical principles that have their origins in the Declaration of Helsinki 

Food and Drug Administration (FDA) Code of Federal Regulation (CFR):
o
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects
o
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators
o
Title 21CFR Part 56, Institutional Review Boards
o
Title 21CFR Part 312, Investigational New Drug Application
o
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the 
protocol, and shall be formally documented as such.
As the Contract Research Organization (CRO) Representative, I understand that my 
signature constitutes agreement and understanding of acceptance of the defined and 
contracted sponsor responsibilities as defined by the protocol, applicable Clinical Trial 
Agreements (CTA), and/or business contracts.  Additionally, my signature constitutes my 
understanding and agreement that any changes to the protocol, CTA, or contracts shall be 
implemented with the Sponsor’s review and approval prior to implementation.
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted Sponsor responsibilities to the 
CRO and the Principal Investigator as defined by the protocol, applicable Clinical Trial 
Agreements (CTA), and/or business contracts, but does not in any capacity relieve me of my 
responsibilities as the Sponsor.  Additionally, my signature constitutes my understanding and 
agreement that any changes to the protocol, CTA, or contracts shall be implemented timely 
with my review and approval prior to implementation.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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Clinical Study Principal Investigator Signature Form
A Phase II Study of the Combination of LY3023414 and Necitumumab after 
First-Line Chemotherapy for Metastatic Squamous Non-small Cell 
Carcinoma of the Lung
SCRI INNOVATIONS STUDY NUMBER:
LUN 288
SPONSOR STUDY NUMBER:
I6A-MC-CBBE
DATE FINAL:
27 February 2015
AMENDMENT NUMBER:
1
AMENDMENT DATE:
08 April 2015
AMENDMENT NUMBER:
2
AMENDMENT DATE:
23 November 2015
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol.
__________________________
__________________________         ______________
Principal Investigator Name
Principal Investigator Signature
Date


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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LUN 288 Clinical Study Summary of Changes
AMENDMENT NUMBER:
2
AMENDMENT DATE:        23 November 2015
Section 3.2 Exclusion Criteria and Synopsis
3. Patients who have received any other investigational agents, chemotherapy, biologic 
therapy, or radiation therapy (including whole brain radiation) within 28 days prior to 
Day 1 of Cycle 1.  For investigational, chemotherapy, or biologic therapy, patients will be 
allowed on study if 5 half-lives or greater have elapsed since last dose of drug or 28 days, 
whichever is shorter. Treatment with limited radiation, including cyberknife, is allowed 
if completed ≥ 2 weeks prior to first study treatment, with approval of the medical 
monitor.
4. History of brain metastases unless irradiated ≥ 2 weeks prior to first study treatment and 
stable without requirement of corticosteroids.
16. The patient has a history of arterial thromboembolic event (ATE) or venous 
thromboembolic event (VTE) within 3 months prior to study enrollment.  Patients with 
history of VTE beyond 3 months prior to study enrollment can be enrolled if they are 
appropriately treated with low molecular weight heparin (LMWH).History of arterial or 
venous embolism within 3 months prior to study enrollment.  If the embolism occurred 
>3 and <6 months, the patient is eligible provided appropriate treatment according to 
institutional standard of care is ensured.
Section 5.1.1 Treatment Plan
Patients should take the morning and evening doses of LY3023414 approximately 12 hours 
apart (preferably within a 10- to 14-hour range).  LY3023414 will be taken in the morning and 
again 12 hours later in the evening.
Section 5.1.2 Necitumumab
All patients will receive 800 mg of necitumumab by IV over a minimum of 50 minutes on Days 
1 and 8 of each 21-day cycle.  
Section 5.4.1 Samples for Pharmacogenetic Biomarkers
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 
association with response to LY3023414 and necitumumab.  These investigations may be limited 
to a focused candidate gene study or, if appropriate, genome wide analysis may be performed to 
identify regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker 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.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015 
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LUN 288 Clinical Study Summary of Changes
AMENDMENT NUMBER:
2
AMENDMENT DATE:        23 November 2015
Section 5.4.1 Samples for Pharmacogenetic Biomarkers
Samples will be destroyed according to a process consistent with local regulation.
It is possible that biomarker data has already been generated from samples that were collected 
and analyzed prior to enrolling in this trial. This may include data generated from genetic 
analyses. If available, this data may be requested from medical records for use in the research 
described in this section.
Section 5.6 Samples for Pharmacogenomic Research
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, 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 ethical review boards (ERBs) allow, a blood/saliva sample will be collected for 
pharmacogenetic analysis.  
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 association with response to LY3023414 and necitumumab.  These 
investigations may be limited to a focused candidate gene study or, if appropriate, genome-
wide analysis may be performed to identify regions of the genome associated with the 
variability observed in drug response.  The pharmacogenetic biomarker 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.
Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor.  The sample and any data 
generated from it can only be linked back to the patient by investigator site personnel.
Section 6.1.1 Hypersensitivity/Infusion Related Reactions
As a routine precaution each visit, patients treated with necitumumab should be closely 
monitored for signs and symptoms indicative of a hypersensitivity/IRR 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 (epinephrine, prednisolone equivalents, etc.) available.
Section 6.1.3 Hypomagnesemia
Hypomagnesemia has been reported with necitumumab cetuximab therapy and is considered to 
be a class effect with EGFR-targeting antibodies (as with panitumumab and cetuximab).


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015 
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LUN 288 Clinical Study Summary of Changes
AMENDMENT NUMBER:
2
AMENDMENT DATE:        23 November 2015
Section 7.2 Baseline Study Assessments
The physical examination, vital signs, ECOG PS, CBC including differential and platelets, 
fasting CMP, urine dipstick, PT/INR, biomarker blood sample, and HbA1c blood sample 
should be done ≤ 7 days prior to initiation of treatment.  However, if these initial examinations 
are obtained within 72 hours prior to the initiation of treatment they do not have to be 
repeated.  
≤ 4 weeks prior to initiation of treatment

CT/MRI of brain if a patient has known brain metastases or if clinically indicated.only 
if the patient has a history of CNS metastasis
Section 7.3.1 Cycle 1– Day 1 and Appendix E

PGx blood sample (if the sample is not collected Cycle 1 Day 1, it can be collected 
anytime during Cycle 1 or Cycle 2)
Section 7.3.1 Cycle 1– Day 1 and Section 7.3.3 Cycle 2 and all Subsequent Cycles - Day 1

Immunogenicity blood sample ± 15 minutes (pre-dose of LY3023414 and necitumumab 
[see Table 2 and Table 3]).  In the event of an IRR, sampling as close to the onset of the 
reaction as possible, at the resolution of the event, and 30 days following the event.
Section 11.2.1 Adverse Event and Serious Adverse Event Reporting
Prior to Administration of Study Drug(s)
Although all AEs after signing the ICF are recorded in the CRF, SAE reporting begins after 
the patient has signed the ICF and has received study treatment.  However, if an SAE occurs 
after signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it 
is considered reasonably possibly related to study procedures.
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the informed consent document.  For patients who do not 
enroll in the study (that is, receive at least 1 dose of study drug), only AEs and SAEs related to 
protocol procedures are required to be collected.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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LUN 288/I6A-MC-CBBE PROTOCOL SYNOPSIS
Title of Study:
A Phase II Study of the Combination of LY3023414 and Necitumumab after First-Line 
Chemotherapy  for Advanced or Metastatic Squamous Non-small Cell Carcinoma of the 
Lung
SCRI Innovations 
Study Number:
LUN 288
Sponsor Number:
I6A-MC-CBBE
Sponsor:
Eli Lilly and Company, Indianapolis, IN
Study Duration:
The total duration of the study is planned to include 12 
months enrolment, and approximately 6 months active 
treatment followed by about 2 years of survival follow up.
Phase of Study:  II
Study Centers:
This study will be conducted at approximately 14 sites.
Number of 
Patients:
Approximately 48 evaluable patients with histologically-confirmed advanced or metastatic 
squamous non-small cell lung cancers (NSCLC), with progressive disease after receiving a 
platinum-based chemotherapy regimen.
Objectives:
Primary Objective
The primary objective of this study is:

To evaluate the 6-month disease control rate (DCR) in patients receiving the 
combination of LY3023414 and necitumumab after first-line platinum-based 
chemotherapy regimen for advanced or metastatic squamous non-small cell 
carcinoma of the lung.
Secondary Objectives
The secondary objectives of this study are to:

To establish that the doses of LY3023414 and necitumumab being studied are safe 
and well-tolerated when administered in combination. 

To characterize exposure of necitumumab and LY3023414 when administered in 
combination.

To evaluate additional measures of efficacy including overall response rate (ORR), 
progression-free survival (PFS), and overall survival (OS) of the combination of 
LY3023414 and necitumumab after first-line platinum-based chemotherapy for 
advanced or metastatic squamous non-small cell carcinoma of the lung.
Exploratory Objective
The exploratory objective of this study is: 

To potentially identify biomarkers (including but not limited to biomarkers of the 
EGFR and PI3K/mTOR pathways) associated with clinical efficacy and disease 
progression in this patient population.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015 
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LUN 288/I6A-MC-CBBE PROTOCOL SYNOPSIS
Study Design:
This is a Phase II single-arm, open-label, clinical study of the combination of LY3023414 
(200 mg orally BID) and necitumumab (800 mg administered IV on Day 1 and 8 of each 21-
day cycle) in patients with previously treated advanced or metastatic squamous non-small 
cell carcinoma of the lung.  
Since the combination of LY3023414 and necitumumab will be given for the first time to 
humans, a safety lead-in will be conducted.  After at least 6 patients (lead-in cohort) have 
been treated for a full cycle, a Safety Internal Monitoring Committee (SIMC) will conduct a 
review of the safety and available PK data to evaluate the safety and PKs of the 
combination.  If 2 (or more) of 3 or 2 (or more) of 6 patients in the lead-in cohort experience 
dose-limiting toxicities (DLTs) as defined in Section 5, 3 to 6 additional patients will be 
treated at a lower dose of study drug(s) following discussion of the safety data by the SIMC 
and assessed for DLTs.  If there is a safety concern or PK interaction deemed to be clinically 
significant by the SIMC, the SIMC may recommend enrollment of approximately 6 
additional patients to further evaluate the safety of the combination, or explore other doses 
of LY3023414 in combination with necitumumab.  In the case of unacceptable and/or 
unmanageable toxicity of the combination at the intended dose level, the SIMC may decide 
to discontinue or modify the study (e.g. proceed with a lower dose level of study drug(s)
tolerated in combination).
The total number of evaluable patients needed from the lead-in and the post lead-in cohort is 
approximately 48, with a planned interim analysis after 24 patients have completed 6 months 
of follow-up.  An interim analysis will be performed purely for the purpose of detecting an 
efficacy signal, and not for the purpose of stopping recruitment.  .
Cycles will be 21 days in length.  Patients will be treated until disease progression as defined 
by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or they develop an 
unacceptable toxicity requiring discontinuation of the drug, or patient/physician choice.  
Patients will be evaluated for response to treatment after every 2 cycles.
Study Drugs, 
Doses, and Modes
of Administration:
Necitumumab 800 mg will be administered by IV on Day 1 and 8 of each cycle.
LY3023414 200 mg will be administered orally (PO) twice a day (BID).


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015 
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LUN 288/I6A-MC-CBBE PROTOCOL SYNOPSIS
Inclusion Criteria:
1.
Histologically confirmed squamous advanced NSCLC (Stage IV).
2.
Patients must have progressed on one prior line of platinum-based 
chemotherapy in the advanced or metastatic setting.  (Immunotherapy, such as 
but not limited to PD-1/PDL-1 inhibitors, will not be considered a line of 
chemotherapy.)
3.
Measurable disease as measured by RECIST criteria v 1.1 (Appendix F).
4.
Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 
1 (Appendix A).
5.
Able to swallow the study drugs whole.
6.
Resolution of side effects from prior treatment, including neuropathy, to 
CTCAE Grade 1 or baseline (with the exception of alopecia).
7.
Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1500/μL

Platelets ≥100,000/µL

Hemoglobin ≥ 8 g/dL
8.
Adequate liver function defined as:

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 x the upper limit of normal (ULN).  If the liver has tumor involvement, 
AST and ALT equaling ≤5 times ULN are acceptable.

Total bilirubin ≤1.5 x ULN (or total bilirubin ≤3.0 x ULN with direct 
bilirubin within normal limits in subjects with well documented Gilbert’s 
Syndrome or a similar syndrome involving slow conjugation of bilirubin).
9.
Adequate renal function defined as serum creatinine ≤1.5 mg/dL OR creatinine 
clearance ≥45 mL/min by Cockcroft-Gault formula for patients with serum 
creatinine > 1.5x ULN.
10. Adequate coagulation parameters, defined as International Normalization Ratio 
(INR) ≤2.  Patients with history of blood clot may receive anticoagulation with 
low molecular weight heparin, central line prophylaxis-dose warfarin, or anti-
factor Xa agents.
11. Women of childbearing potential must have a negative serum or urine 
pregnancy test performed ≤7 days prior to start of treatment.  Women of 
childbearing potential or men with partners of childbearing potential must use 
effective birth control measures during treatment and during the 3 months 
following completion of study treatment.  If a woman becomes pregnant or 
suspects she is pregnant while participating in this study, she must agree to 
inform her treating physician immediately (Appendix D).
12. Life expectancy ≥ 3 months.
13. Age ≥18 years.
14. Willingness and ability to comply with study and follow-up procedures.
15. Ability to understand the nature of this study and give written informed consent.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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LUN 288/I6A-MC-CBBE PROTOCOL SYNOPSIS
Exclusion 
Criteria:
1.
Patients who have received > 1 prior line of chemotherapy in the advanced or 
metastatic setting.  (Immunotherapy, such as but not limited to PD-1/PDL-1 
inhibitors, will not be considered a line of chemotherapy.)
2.
Prior treatment with a PI3K/mTOR inhibitor, EGFR inhibitor, and/or 
necitumumab.
3.
Patients who have received any other investigational agents, chemotherapy, 
biologic therapy, or radiation therapy (including whole brain radiation) within 28 
days prior to Day 1 of Cycle 1.  For investigational, chemotherapy, or biologic 
therapy, patients will be allowed on study if 5 half-lives or greater have elapsed 
since last dose of drug or 28 days, whichever is shorter.  Treatment with limited 
radiation, including cyberknife, is allowed if completed ≥ 2 weeks prior to first 
study treatment, with approval of the medical monitor.
4.
History of brain metastases unless irradiated prior to first study treatment and 
stable without requirement of corticosteroids.
5.
Have serious pre-existing medical conditions, including major surgery within 30 
days, (at the discretion of the investigator).
6.
Have insulin-dependent diabetes mellitus.  Patients with a type 2 diabetes mellitus 
are eligible if adequate control of blood glucose level is obtained by oral anti-
diabetics as documented by HbA1c < 7%.
7.
Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral 
therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, Grade ≥2 
diarrhea, and malabsorption syndrome).
8.
Have a history of New York Heart Association (NYHA) Class ≥3 (Appendix B), 
Canadian Cardiovascular Society (CCS) Grade ≥ 3 (Appendix C), corrected QT 
(QTc) interval > 450 ms on screening electrocardiogram (ECG) per Fridericia’s 
formula at several consecutive days of assessment, unstable angina, or myocardial 
infarction (MI) in 6 months prior to study drug administration.
9.
Women who are pregnant or breast-feeding.
10. Clinically significant electrolyte imbalance ≥ Grade 2.
11. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low 
molecular weight heparin and oral Xa inhibitors are allowed.
12. Have initiated treatment with bisphosphonates or approved receptor activator of 
nuclear factor kappa-B ligand (RANK-L) targeted agents (e.g. denosumab) ≤28 
days prior to Day 1 of Cycle 1.


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015 
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LUN 288/I6A-MC-CBBE PROTOCOL SYNOPSIS
Exclusion 
Criteria, contd.:
13. Concurrent serious infection requiring parenteral antibiotic therapy.
14. Have a second primary malignancy that in the judgment of the investigator and 
Medical Monitor may affect the interpretation of results.
15. Have clinical evidence of concomitant infectious conditions including early signs 
of ongoing or active infection, tuberculosis or known infection with the human 
immunodeficiency virus (HIV) or hepatitis (HAV, HBV or HCV).  Special 
attention should be paid to early signs of pulmonary infections in patients with 
large cavitary lesions.
16. The patient has a history of arterial thromboembolic event (ATE) or venous 
thromboembolic event (VTE) within 3 months prior to study enrollment.  Patients 
with history of VTE beyond 3 months prior to study enrollment can be enrolled if 
they are appropriately treated with low molecular weight heparin (LMWH).
17. Patients with known inherited thrombophilia (such as Factor V Leiden, 
Prothrombin 20210 mutation, protein C, protein S or antithrombin 3 deficiency; 
no screening required).
18. Psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol.
Correlative 
Testing:
Blood and tumor samples will be collected and may be evaluated for biomarkers 
including but not limited to the PI3K/mTOR and EGFR pathways.
Statistical 
Methodology:
This is a Phase II open-label, non-randomized clinical study of the combination of LY3023414 
(200 mg orally BID) and necitumumab (800 mg administered IV on Day 1 and 8 of each 21-
day cycle) in patients with previously treated advanced or metastatic squamous non-small cell 
carcinoma of the lung.  
 
 
  Based upon a 1-sided type I error rate of 20% and 
power of 90% the total sample size required to test the null hypothesis is 48 evaluable patients. 
A planned interim analysis will take place when 24 patients are evaluable for the primary 
endpoint, including the initial 6 patients treated at that dose to establish the safety and 
pharmacokinetics of the combination. The O’Brien Fleming spending function is 0.067 at the 
interim analysis and 0.131 at the final analysis. 
 
 
CCI
CCI


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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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LUN 288/I6A-MC-CBBE CONTACT INFORMATION
CRO Contact Information:
SCRI Innovations
3322 West End Avenue, Suite 900
Nashville, TN  37203
Study Chair:
, MD
Sarah Cannon Research Institute
3322 West End Avenue, Suite 900
Nashville, TN  37203
Medical Monitor:
M.D.
SCRI Innovations
3322 West End Avenue, Suite 900
Nashville, TN  37203
 
Sponsor Contact Information:
MD, PhD
Eli Lilly and Company
Kolblgasse 8-10
A-1030 Vienna, Austria
Sponsor Safety Dept. Fax #:
Regulatory Phone # / Fax #:
Regulatory Email:
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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase
ALT (SGPT)
Alanine aminotransferase
ANC
Absolute neutrophil count
AST (SGOT)
Aspartate aminotransferase
BID
Twice a day
CBC
Complete blood count
CFR
Code of Federal Regulations
CI
Confidence interval
CMP
Comprehensive metabolic profile
CR
Complete response
CT
Computerized tomography
DCR
Disease control rate
DP
Drug product
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form 
EOI
End of infusion
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
INR
International Normalized Ratio
IRB
Institutional Review Board
IRR
Infusion-related reaction
IV
Intravenous
LDH
Lactate dehydrogenase
MTD
Maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
Non-small cell lung cancer
OS
Overall survival
PD
Progressive disease
PDx
Pharmacodynamic
PHI
Protected health information
PFS
Progression-free survival
PK
Pharmacokinetic
PO
By mouth
PR
Partial response
QD
Once a day
RR
Response rate


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LIST OF ABBREVIATIONS (continued)
SAE
Serious adverse event
SCRI
Sarah Cannon Research Institute
SD
Stable disease
SIMC
Safety Internal Monitoring Committee
ULN
Upper limit of normal


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TABLE OF CONTENTS
1.
INTRODUCTION .............................................................................................23
1.1
Background........................................................................................................23
1.2
Treatment for Non-Small Cell Lung Cancer .......................................................23
1.3
LY3023414........................................................................................................24
Nonclinical Toxicology and Safety Pharmacology .............................................24
1.3.1
Nonclinical Pharmacokinetics/Pharmacodynamics .............................................25
1.3.2
Clinical Experience with LY3023414.................................................................25
1.3.3
1.4
Necitumumab.....................................................................................................26
1.5
Rationale for the Study.......................................................................................27
2.
STUDY OBJECTIVES......................................................................................28
2.1
Primary Objective ..............................................................................................28
2.2
Secondary Objectives .........................................................................................28
2.3
Exploratory Objectives.......................................................................................28
3.
STUDY PATIENT POPULATION AND DISCONTINUATION......................29
3.1
Inclusion Criteria................................................................................................29
3.2
Exclusion Criteria ..............................................................................................30
3.3
Discontinuation from Study Treatment ...............................................................31
4.
STUDY REGISTRATION.................................................................................32
5.
STUDY DESIGN...............................................................................................32
5.1
Treatment Plan...................................................................................................36
LY3023414........................................................................................................36
5.1.1
Necitumumab.....................................................................................................36
5.1.2
5.2
Treatment Duration ............................................................................................37
5.3
Concomitant Medications...................................................................................37
Permitted Concomitant Medications ...................................................................37
5.3.1
Prohibited Concomitant Medications ..................................................................38
5.3.2
Concomitant Medications to be avoided .............................................................38
5.3.3
5.4
Correlative Studies .............................................................................................38
Samples for Biomarkers .....................................................................................39
5.4.1
5.5
Pharmacokinetic Assessments ............................................................................40
Bio-Analytical Assays for Drug Concentration Measurements 
5.5.1
Pharmacokinetics Samples .................................................................................41
Samples for Immunogenicity Research...............................................................41
5.5.2
5.6
Samples for Pharmacogenomic Research ...........................................................44


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6.
DOSE MODIFICATIONS .................................................................................44
6.1
Necitumumab Non-Hematologic Toxicities........................................................45
Hypersensitivity/Infusion-Related Reactions ......................................................45
6.1.1
Skin Reactions ...................................................................................................48
6.1.2
Hypomagnesemia...............................................................................................50
6.1.3
Thromboembolic Events ....................................................................................50
6.1.4
7.
STUDY ASSESSMENTS AND EVALUATIONS.............................................50
7.1
Overview ...........................................................................................................50
7.2
Baseline Study Assessments...............................................................................50
7.3
Study Treatment Assessments ............................................................................51
Cycle 1 – Day 1..................................................................................................51
7.3.1
Cycle 1 – Day 8..................................................................................................52
7.3.2
Cycle 2 and all Subsequent Cycles – Day 1 (±72 hours) .....................................53
7.3.3
Cycle 2 and all Subsequent Cycles – Day 8 ........................................................53
7.3.4
7.4
Response Assessment Prior to Cycle 3 and After Every 2 Cycles .......................54
7.5
End of Treatment Visit .......................................................................................54
7.6
Follow-up...........................................................................................................55
Follow-up for Patients Who Discontinue Prior to Disease Progression ...............55
7.6.1
Survival Follow-Up............................................................................................55
7.6.2
8.
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION.............................................................................55
8.1
LY3023414........................................................................................................55
Labeling, Packaging, and Supply........................................................................55
8.1.1
Precautions and Risks Associated with LY3023414 ...........................................56
8.1.2
8.2
Necitumumab.....................................................................................................57
Labeling, Packaging, and Supply........................................................................57
8.2.1
Preparation and Administration of Necitumumab ...............................................57
8.2.2
Precautions and Risks Associated with Necitumumab ........................................58
8.2.3
8.3
Accountability for All Study drugs .....................................................................58
9.
RESPONSE EVALUATIONS AND MEASUREMENTS..................................58
10.
STATISTICAL CONSIDERATIONS................................................................59
10.1
Statistical Design................................................................................................59
10.2
Sample Size Considerations ...............................................................................59
10.3
Analysis Population ...........................................................................................59
10.4
Data Analysis.....................................................................................................59
Demographics and Baseline Characteristics........................................................59
10.4.1


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Efficacy Analysis ...............................................................................................59
10.4.2
Safety Analysis ..................................................................................................61
10.4.3
Pharmacokinetics ...............................................................................................62
10.4.4
10.5
Analysis Time Point...........................................................................................62
Final Analysis ....................................................................................................62
10.5.1
Planned Interim Analysis ...................................................................................62
10.5.2
Safety Review ....................................................................................................62
10.5.3
11.
SAFETY REPORTING AND ANALYSES .......................................................63
11.1
Adverse Events ..................................................................................................63
11.2
Serious Adverse Events......................................................................................65
Adverse Event and Serious Adverse Event Reporting.........................................66
11.2.1
11.3
Complaint Handling ...........................................................................................67
12.
QUALITY ASSURANCE AND QUALITY CONTROL ...................................67
12.1
Monitoring .........................................................................................................67
12.2
Audits and Inspections .......................................................................................67
13.
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS............68
13.1
Institutional Review Board Approval .................................................................68
13.2
Regulatory Approval ..........................................................................................68
13.3
Informed Consent...............................................................................................68
Confidentiality ...................................................................................................69
13.3.1
13.4
Financial Information.........................................................................................70
14.
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY........70
14.1
Amendments to the Protocol ..............................................................................70
14.2
Documentation Required to Initiate the Study ....................................................71
14.3
Study Documentation and Storage......................................................................71
14.4
Data Collection ..................................................................................................73
14.5
Disclosure and Publication Policy ......................................................................73
15.
REFERENCES ..................................................................................................75
16.
APPENDICES ...................................................................................................79


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LIST OF TABLES
Table 1
Biomarker Sample Collection Times .....................................................39
Table 2
Pharmacokinetic and Immunogenicity Sample Collection Times for 
Assessment of LY3023414 and Necitumumab Concentration – Lead-
In Patients .............................................................................................42
Table 3
Pharmacokinetic and Immunogenicity Sample Collection Times for 
Assessment of LY3023414 and Necitumumab Concentration – Post 
Lead-In Patients ....................................................................................43
Table 4
Dose Level Modifications .....................................................................45
Table 5
Infusion-Related Reactions – Management Recommendations ..............47
Table 6
Skin Reactions – Management Recommendations.................................48
LIST OF FIGURES
Figure 1
Study Schema........................................................................................35
LIST OF APPENDICES
Appendix A:
ECOG Performance Status Criteria .......................................................79
Appendix B:
New York Heart Association (NYHA) Classification of Cardiac 
Disease..................................................................................................80
Appendix C:
Canadian Cardiovascular Society (CCS) Angina Grading Scale ............81
Appendix D:
Guidelines for Women of Childbearing Potential and Fertile Male 
Patients .................................................................................................82
Appendix E:
Schedule of Assessments.......................................................................84
Appendix F:
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 ...87
Appendix G:
Drugs That Prolong QT Interval and/or Induce Torsades de Pointes ......91
Appendix H:
List of QT Prolonging Drugs to be Used with Caution...........................92
Appendix I:
Common CYP1A2 Inducers, Substrates for CYP3A4, CYP3A 
Inducers and Inhibitors, and P-gp/CYP3A Dual Inhibitors.....................94


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1.
INTRODUCTION
1.1
Background
Lung cancer is the second most common cancer in both men and women, after skin cancer.  It is 
estimated that lung cancer accounts for about 13% of all new cancers, and about 27% of all 
cancer deaths.  Each year more people die from lung cancer than from prostate, colon, and breast 
cancers combined.  Patients with advanced or metastatic non-small cell lung cancer (NSCLC)
continue to have a poor prognosis with standard treatments (Rooney et al. 2013).  Squamous cell 
carcinoma is often linked to a history of smoking and comprises 25% to 30% of all lung cancers 
(American Cancer Society 2014).
1.2
Treatment for Non-Small Cell Lung Cancer
Platinum-containing chemotherapy for first-line treatment alone or in combination with other 
cytotoxic drugs is standard treatment (American Society of Clinical Oncology Guidelines 2014).  
Specifically for squamous cell lung cancers, first-line therapy options include platinum-taxane 
combinations and platinum-gemcitabine combinations, as pemetrexed has little efficacy for 
squamous cell lung cancers (Scagliotti et al. 2008, Syrigos et al. 2010).  First-line combination 
chemotherapy is typically limited to 4 to 6 cycles of active therapy, followed by single agent 
maintenance therapy per National Comprehensive Cancer Network guidelines; however, a 
definitive standard of care has not been defined.  Upon progression, second-line chemotherapy 
options have produced response rates in the 10% range, progression-free survival (PFS)/time to 
progression (TTP) in the 3-month range, and overall survival (OS) in the 7-month range (Dancey 
et al. 2004).  Docetaxel, an FDA-approved taxane for the treatment of second-line advanced or 
metastatic NSCLC, has a response rate of 10.8% with 100 mg/m2 and 6.7% with 75 mg/m2
dosing, respectively, demonstrating a benefit to patients with disease that has relapsed or 
progressed after first line treatment (Shepherd et al. 2000, Fossella et al. 2000).
Molecularly targeted therapies, where treatment is based on mutations seen in individual patient 
tumors, have increased the survival benefit for subsets of NSCLC patient populations (Kris et al. 
2014). Specifically, therapies targeting EGFR mutations and ALK translocations have shown 
benefit, as evidenced by the approvals of erlotinib (Mok et al. 2009, Mitsudomi et al. 2010,
Maemondo et al. 2010, Rosell et al. 2012) and crizotinib (Kwak et al. 2010, Shaw et al. 2011,
Camidge et al. 2012, Shaw et al. 2013).  Therapies which target mutations in the MAPK and 
PI3K pathway are also showing promise, but have not yet shown definitive efficacy in 
randomized trials.  However, significant molecularly targeted breakthroughs for patients with 
squamous cell lung cancers have not been achieved, in part, due to the low rates of EGFR 
mutation and ALK translocation in squamous cell lung cancers (Gold et al. 2012).  
The PI3K/AKT signaling pathway is central to NSCLC growth and survival (Sacco et al. 2014).  
Approximately 6.5% of squamous cell lung cancer patients have PI3K mutations. An additional 
33% have PI3K copy number gain.  In addition, as high as 70% of squamous cell lung cancers 
have shown loss of PTEN, with PTEN mutation occurring in 10% (Kim et al. 2013).  The PI3K 
pathway is therefore a promising target for treatment (Yamamoto et al. 2008, Herzog et al. 
2013).


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The REVEL trial (Lilly Study I4T-MC-JVBA), a randomized Phase III study of ramucirumab 
plus docetaxel versus placebo plus docetaxel for second -line treatment of stage IV NSCLC after 
disease progression on platinum-based therapy showed an increase in PFS and disease control 
rate (DCR) with the combination of ramucirumab and docetaxel over docetaxel alone.  
Ramucirumab is a human IgG1 monoclonal antibody that inhibits VEGFR-2.  The combination 
therapy in this trial resulted in an overall DCR of 64% and median PFS of 4.5 months.  These 
findings were largely consistent across the subgroups of squamous and non-squamous lung 
cancers (Garon et al. 2014).  
 
1.3
LY3023414
LY3023414 is an orally available, small molecule dual kinase inhibitor of class I PI3K isoforms 
and mTOR with good solubility across a wide pH range. In vitro kinase studies have shown that 
LY3023414 binds to the adenosine triphosphate (ATP) active site of PI3K to competitively 
inhibit phosphorylation of PIP2 at low nanomolar concentrations. In nonclinical studies, 
LY3023414 has demonstrated potent in vivo target inhibition that was linked to potent antitumor 
efficacy.  The nonclinical toxicology profile of LY3023414 has enabled a safe clinical starting 
dose, and a benefit-risk profile acceptable for cancer treatment, with toxicities observed in 
animal species that are manageable, readily monitored, and likely reversible.  The Phase I first-
in-human study is currently underway and is showing this drug to be well-tolerated with 
preliminary signs of clinical activity (see Investigator’s Brochure [IB] and Section 1.3.3).
Nonclinical Toxicology and Safety Pharmacology
1.3.1
1.3.1.1
Nonclinical Toxicology
LY3023414 was evaluated in nonclinical toxicology studies up to 1 month in duration using 
daily oral dosing in rats and dogs to characterize the toxicity.  Based on results from nonclinical 
studies in the rat and the dog, toxicities patients may experience include (but are not limited to) 
gastrointestinal toxicity, bone marrow and lymphoid organ toxicity (decreases in lymp hocytes), 
sores/scabbing of the skin, and adrenal toxicity.  These toxicity effects are anticipated to be 
reversible.  Pharmacologic effects of PI3K/mTOR inhibition related to glucose metabolism have 
also been observed, including hyperinsulinemia, hyperglycemia, and QT interval prolongation in 
nonclinical studies.  In a rat embryo-fetal developmental pilot study of LY3023414, embryo -fetal 
lethality was seen along with an increase in fetal and litter incidence of external, visceral, and 
skeletal malformations.
For additional details on nonclinical toxicology data, see Section 5.2.1 of the IB.
1.3.1.2
Nonclinical Efficacy Pharmacology Summary
LY3023414 is a potent selective inhibitor of the class I PI3K isoforms, mTOR and DNA-PK, 
with selectivity in kinase enzyme assays as an ATP competitive inhibitor of PI3K(inhibition 
binding constant [Ki] of
). LY3023414 demonstrated inhibitory activity against 
PI3K/mTOR pathway targets in vitro and in vivo as measured by phosphoprotein levels from 
cultured cells and tumor xenografts. LY3023414 showed antiproliferative and cell-cycle 
arresting effects in cultured cancer cells, and anti-angiogenesis activity via inhibition of in vitro
CCI
CCI


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vascular cord formation.  LY3023414 has excellent solubility and oral bioavailability across a 
wide pH range, allowing for simple suspension formulations to be used for oral administration in 
nude mice.  In xenograft tumor models, LY3023414 demonstrated dose-and time-dependent 
target inhibition, as well as antitumor efficacy in a wide range of tumor models (including renal 
cancer and NSCLC).  The mouse pharmacokinetic (PK)/pharmacodynamics (PDx) model 
indicates a direct inhibition of downstream target phosphoproteins (such as, phospho-AKT
[pAKT], phospho -0S6K [p70S6K]).  LY3023414 has potential for combination with standard of 
care agents to produce synergistic effects in cell culture and in vivo xenograft models.
Nonclinical Pharmacokinetics/Pharmacodynamics
1.3.2
Bioavailability of LY3023414 was 
 in dogs, and the clearance was less than hepatic blood 
flow.  No accumulation of LY3023414 was noted following repeated dosing to rats and dogs.  
Also, no consistent gender differences in toxicokinetic parameters were observed in rats or dogs 
throughout a 1-month study.  In vivo metabolism data showed that LY3023414 is metabolized 
predominantly via oxidation in rats and via oxidation and glucuronidation in dogs.  In both 
species, LY3023414 was the largest circulating entity in plasma.  Overall, clearance of 
LY3023414 in rats was primarily via metabolism while clearance in dogs involved metabolism 
as well as elimination via feces and urine.  Fecal excretion was the major route of elimination for 
LY3023414-related radioactivity in both species.
Clinical Experience with LY3023414
1.3.3
One Phase I study I6A-MC-CBBA (Study CBBA) of LY3023414 is ongoing.  Study CBBA is a 
multicenter, nonrandomized, open-label, First-in-Human dose escalation study followed by 
cohort expansion of oral LY3023414 in patients with advanced and/or metastatic cancer.  Study 
CBBA was designed to evaluate the safety and tolerability of LY3023414 administered orally 
over 21 days (one cycle). 
As of 26 September 2014, a total of 47 patients have received LY3023414 in the first-human-
dose Study CBBA. Of these patients, a total of 40 patients (83%) experienced at least 1 possibly 
study drug-related, treatment-emergent adverse event (TEAE).  The most common possibly 
LY3023414-related AEs reported in at least 10% of patients included nausea (37.5%), fatigue 
(31.3%), vomiting (27.1%), diarrhea (16.7%), decreased appetite (14.6%), anemia (14.6%), 
stomatitis (12.5%), and asthenia (10.4%).  Most of these events were graded as mild or moderate 
by the investigators. 
Dose-limiting toxicities (DLTs) for LY3023414 daily (QD) dosing have been reported at 450 mg 
LY3023414 in 3 out of 3 patients, including 1 case each of thrombocytopenia (Grade 4), 
hypotension (Grade 3), and hyperkalemia (Grade 3). Therefore, a dose of 325 mg LY3023414 
was defined as the maximum tolerated dose (MTD) for QD dosing. For twice daily (BID)
dosing, DLTs were observed in 3 out of 4 patients at the 250 mg BID LY3023414 dose in the 
form of hypophosphatemia (Grade 4), fatigue, and mucositis (Grade 3; all n = 1). At the next 
lower dose level of 200 mg BID in the dose escalation phase, 1 out of 6 patients experienced a 
DLT in the form of nausea (Grade 2; n = 1). Therefore, a dose of 200 mg LY3023414 was 
defined as the MTD for BID dosing.
CCI


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At doses up to and including the MTD for QD and BID dosing (n = 31 patients, dose escalation 
phase), no study drug related Grade 4 AEs have been reported. Six possibly related Grade 3 AEs 
have been observed in those patients, including 1 case each of fatigue, hyperglycemia, 
hypokalemia, neutropenia, hypomagnesemia, and anemia (anemia occurred in a patient entering 
the study with Grade 2 anemia).  LY3023414 200 mg BID was confirmed as the MTD based on 
the safety data on 9 additional patients (part B1 of Study CBBA).  As of 26 September 2014, a 
total of 15 patients have received LY3023414 200 mg BID.
Initial clinical LY3023414 PK data showed that LY3023414 maximum plasma concentration 
(Cmax) and area under the plasma concentration-time curve (AUC∞) increased approximately 
dose-proportionally from 20 to 325 mg QD (that is within the QD dose range determined to be 
safe).  However, the Cmax and AUC∞increase was greater than dose proportional at 450 mg QD 
(i.e., that is at the dose exceeding the MTD).  LY3023414 PK data following repeated BID 
dosing (dose range of 150 to 250 mg BID) were consistent with PK data following 20 to 325 mg 
QD.  LY3023414 mean apparent clearance (CL/F) and mean apparent volume of distribution
(Vz/F) were calculated to be 85 L/hr (CV% 56.8%) and 237 L (CV% 53.9%), respectively,
across the 20 to 325-mg dose range based on Day 1 data.  This clearance and volume lead to 
mean half-life (t1/2)of 1.93 hours (coefficient of variation CV% = 42.9%; n = 38 for all doses 
combined within a dose-proportionality range of 20 mg to 325 mg).  
The relative contribution of microsomal CYP-mediated clearance of LY3023414 was studied in 
vitro using human liver microsomes.  Based on a substrate depletion approach, CYP 3A and 
CYP1A2 are responsible for 82% and 18% of hepatic CYP-mediated clearance of LY3023414, 
respectively.  No in vivo data are yet available. 
The recent data from study CBBA indicate that LY3023414 is a weak inhibitor of CYP3A4.
Concomitant administration of LY3023414 and midazolam lead to increase in midazolam 
exposure (fold increase: mean 1.459 [CV 30.5 %] [90% CI 1.21 – 1.76]).  Hence LY3023414 
may lead to increase in exposure of drugs predominantly cleared by CYP3A4.  
Biomarker assessment demonstrated target inhibition as measured by p4EBP1 inhibition in 
peripheral blood mononuclear cells (PBMC) at LY3023414 dose levels greater or equal to 150 
mg QD in a dose related manner.  With respect to anti-tumor activity, clinical benefit was 
observed in patients treated on both schedules of LY3023414, including 1 patient with a 
confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors 
(RECIST) v 1.1 (Eisenhauer et al. 2009) and 10 additional patients (26.3%) who demonstrated a 
decrease in their tumor target lesion as best response to LY3023414 monotherapy in the dose-
escalation part of Study CBBA (see Section 6.2.2 of the IB).
Based on the safety and tolerability, PK, target inhibition, and preliminary activity data outlined 
above, the recommended dose for LY3023414 is 200 mg by mouth (PO) BID.
Additional data are available in the latest LY3023414 Investigator’s Brochure (IB).
1.4
Necitumumab
Necitumumab is a recombinant human monoclonal antibody (mAb) of the immunoglobin G, 
subclass 1, which blocks the ligand binding site of the epidermal growth factor receptor (EGFR).  
Necitumumab has shown in vivo antitumor activity against a variety of human xenograft tumors, 


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including NSCLC. Preclinical studies were conducted using mice with lung cancer xenografts 
(NCI-H1975 and NCI-H292) administered necitumumab as monotherapy. In these studies, 
administration of necitumumab inhibited the growth of both xenograft models; antitumor activity 
was statistically significant for both models at all dose levels.
The necitumumab Phase I program included 2 single-agent dose-escalation Phase I trials in 
Western (I4T-IE-JFCE [JFCE]) and Japanese (I4T-IE-JFCA [JFCA]) patients with advanced 
solid tumors or for which no standard therapy was available.
Study JFCE included 60 patients and investigated necitumumab intravenous (IV) 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.  Safety data from Study CP11-0401JFCE demonstrated that the maximum 
tolerated dose (MTD) of necitumumab is 800 mg once weekly or once every 2 weeks (Kuenen et 
al. 2010).  The major dose limiting toxicity (DLT) was Grade 3 headache.  The most common 
drug-related AEs were typical for this class of agents and consisted of skin reactions, headache, 
nausea/vomiting, and fatigue (mostly of Grades 1 and 2) (for details, see Section 6.2.1.1 of 
necitumumab IB). 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).  
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 I 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 III trial SQUIRE (I4T-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. 2014).  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%).
Additional data are available in the latest necitumumab Investigator’s Brochure (IB)
1.5
Rationale for the Study
Preclinical data has suggested that the PI3K pathway plays a role in the antitumor efficacy of 
EGFR antibodies.  In NSCLC models, acquired cetuximab resistance is mediated by increased 
PTEN instability (Kim et al. 2010).  In head and neck squamous cell carcinoma (HNSCC) 
models, resistance to cetuximab may be bypassed by inhibition of AKT (Rebucci et al. 2011).  In 
patients with colorectal cancer, resistance to cetuximab is increased in patients with PI3K 


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mutations and aberrations in PTEN (Sood et al. 2012).  In addition, internal preclinical data from 
Lilly shows that in squamous patient-derived xenograft models, the combination of necitumumab 
and LY3023414 resulted in improved anti-tumor activity relative to monotherapy with 
necitumumab or LY3023414 alone. 
Based on the need for better treatment options after first-line therapy for patients with squamous 
cell lung cancer, the benefit recently seen with necitumumab, the preclinical synergy of 
LY3023414 and necitumumab, and the favorable safety profile of LY3023414 and 
necitumumab, a combination trial of necitumumab plus LY3023414 in patients with advanced or 
metastatic squamous NSCLC which has relapsed or progressed after first-line treatment with a 
platinum-containing regimen is proposed to explore whether the 6-month DCR with this 
combination will confer a greater benefit than what has been observed for patients with 
squamous histology in the REVEL study (Lilly Study I4T-MC-JVBA).  
2.
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To evaluate the 6-month DCR in patients receiving the combination of LY3023414 and 
necitumumab after first-line platinum-based chemotherapy regimen for advanced or 
metastatic squamous non-small cell carcinoma of the lung.
2.2
Secondary Objectives
The secondary objectives of this study are:

To establish that the doses of LY3023414 and necitumumab being studied are safe and 
well-tolerated when administered in combination. 

To characterize exposure of necitumumab and LY3023414 when administered in 
combination.

To evaluate additional measures of efficacy including overall response rate (ORR), 
progression-free survival (PFS), and overall survival (OS) of the combination of 
LY3023414 and necitumumab after first-line platinum-based chemotherapy for advanced 
or metastatic squamous non-small cell carcinoma of the lung.
2.3
Exploratory Objectives
The exploratory objective of this study is:

To potentially identify biomarkers (including but not limited to biomarkers of the EGFR 
and PI3K/mTOR pathways) associated with clinical efficacy and disease progression in 
this patient population.


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3.
STUDY PATIENT POPULATION AND DISCONTINUATION
3.1
Inclusion Criteria
Patients must meet all of the following criteria in order to be included in the research study:
1. Histologically confirmed squamous advanced NSCLC (Stage IV).
2. Patients must have progressed on one prior line of platinum-based chemotherapy in the 
advanced or metastatic setting.  (Immunotherapy, such as but not limited to PD-1/PDL-1 
inhibitors, will not be considered a line of chemotherapy.)
3. Measurable disease as measured by Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria v 1.1 (Appendix F).
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
(Appendix A).
5. Able to swallow the study drugs whole.
6. Resolution of side effects from prior treatment, including neuropathy, to CTCAE Grade 1 
or baseline (with the exception of alopecia).
7. Adequate hematologic function defined as:
-
Absolute neutrophil count (ANC) ≥1500/μL
-
Platelets ≥100,000/µL
-
Hemoglobin ≥ 8 g/dL
8. Adequate liver function defined as:
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
the upper limit of normal (ULN). If the liver has tumor involvement, AST and 
ALT equaling ≤5 times ULN are acceptable.
-
Total bilirubin ≤1.5 x ULN (or total bilirubin ≤3.0 x ULN with direct bilirubin 
within normal limits in subjects with well documented Gilbert’s Syndrome or a 
similar syndrome involving slow conjugation of bilirubin).
9. Adequate renal function defined as serum creatinine ≤1.5 mg/dL OR creatinine clearance 
≥45 mL/min by Cockcroft-Gault formula for patients with serum creatinine > 1.5x ULN.
10. Adequate coagulation parameters, defined as International Normalization Ratio (INR) 
≤2.  Patients with history of blood clot may receive anticoagulation with low molecular 
weight heparin, central line prophylaxis-dose warfarin, or anti-factor Xa agents.
11. Women of childbearing potential must have a negative serum or urine pregnancy test 
performed ≤7 days prior to start of treatment.  Women of childbearing potential or men 
with partners of childbearing potential must use effective birth control measures during 
treatment and during the 3 months following completion of study treatment.  If a woman 
becomes pregnant or suspects she is pregnant while participating in this study, she must 
agree to inform her treating physician immediately (Appendix D).


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12. Life expectancy ≥ 3 months.
13. Age ≥18 years.
14. Willingness and ability to comply with study and follow -up procedures.
15. Ability to understand the nature of this study and give written informed consent.
3.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1. Patients who have received > 1 prior line of chemotherapy in the advanced or metastatic 
setting.  (Immunotherapy, such as but not limited to PD-1/PDL-1 inhibitors, will not be 
considered a line of chemotherapy.)
2. Prior treatment with a PI3K/mTOR inhibitor, EGFR inhibitor, and/or necitumumab.
3. Patients who have received any other investigational agents, chemotherapy, biologic 
therapy, or radiation therapy (including whole brain radiation) within 28 days prior to 
Day 1 of Cycle 1.  For investigational, chemotherapy, or biologic therapy, patients will be 
allowed on study if 5 half-lives or greater have elapsed since last dose of drug or 28 days, 
whichever is shorter.  Treatment with limited radiation, including cyberknife, is allowed 
if completed ≥ 2 weeks prior to first study treatment, with approval of the medical 
monitor.
4. History of brain metastases unless irradiated prior to first study treatment and stable 
without requirement of corticosteroids.
5. Have serious pre-existing medical conditions, including major surgery within 30 days, (at 
the discretion of the investigator).
6. Have insulin-dependent diabetes mellitus.  Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as 
documented by HbA1c < 7%.
7. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(e.g. ulcerative disease, uncontrolled nausea, vomiting, Grade ≥2 diarrhea, and 
malabsorption syndrome).
8. Have a history of New York Heart Association (NYHA) Class ≥3 (Appendix B), 
Canadian Cardiovascular Society (CCS) Grade ≥ 3 (Appendix C), corrected QT (QTc)
interval > 450 ms on screening electrocardiogram (ECG) per Fridericia’s formula at 
several consecutive days of assessment, unstable angina, or myocardial infarction (MI) in 
6 months prior to study drug administration.
9. Women who are pregnant or breast-feeding.
10. Clinically significant electrolyte imbalance ≥ Grade 2.
11. Currently receiving treatment with therapeutic doses of warfarin sodium.  Low molecular 
weight heparin and oral Xa inhibitors are allowed.


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12. Have initiated treatment with bisphosphonates or approved receptor activator of nuclear 
factor kappa-B ligand (RANK-L) targeted agents (e.g. denosumab) ≤28 days prior to 
Day 1 of Cycle 1.
13. Concurrent serious infection requiring parenteral antibiotic therapy.
14. Have a second primary malignancy that in the judgment of the investigator and Medical 
Monitor may affect the interpretation of results.
15. Have clinical evidence of concomitant infectious conditions including early signs of 
ongoing or active infection, tuberculosis or known infection with the human 
immunodeficiency virus (HIV) or hepatitis (HAV, HBV or HCV). Special attention 
should be paid to early signs of pulmonary infections in patients with large cavitary 
lesions.
16. The patient has a history of arterial thromboembolic event (ATE) or venous 
thromboembolic event (VTE) within 3 months prior to study enrollment.  Patients with 
history of VTE beyond 3 months prior to study enrollment can be enrolled if they are 
appropriately treated with low molecular weight heparin (LMWH).
17. Patients with known inherited thrombophilia (such as Factor V Leiden, Prothrombin 
20210 mutation, protein C, protein S or antithrombin 3 deficiency; no screening 
required).
18. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.
3.3
Discontinuation from Study Treatment
Patients will be discontinued from study treatment fo r any of the following reasons:

Disease progression

Irreversible or intolerable AE thought to be related to study drug(s) (e.g. infusion related 
reactions ≥ Grade 3 to necitumumab)

Conditions requiring therapeutic intervention not permitted by the protocol

Intercurrent illness (this will be at the investigator’s discretion)

Inability of the patient to comply with study requirements or lost to follow -up

Patient requests to discontinue treatment

Patient withdraws consent 

Investigator or Sponsor team, for any ethical, medical, or scientific reason, while 
considering the rights, safety, and well-being of the patient(s), stops the study treatment.

Any patient requiring an AE-related dose delay of more than 21 days due to a study drug 
related AE must be discontinued from the study treatment, unless discussed with the 
Medical Monitor.
Refer to Section 7.6 for Follow-Up information.


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4.
STUDY REGISTRATION
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Institutional Review Board (IRB) approval of this protocol and consent form is 
required.  Eligible patients who wish to participate in the study will be enrolled into the study.
Registration must occur prior to the initiation of protocol therapy.  Patient registration will be 
performed by SCRI Innovations and will be outlined in the Study Reference Manual.  
5.
STUDY DESIGN
This is a Phase II single-arm, open-label, clinical study of the combination of LY3023414 (200 
mg orally BID) and necitumumab (800 mg administered IV on Day 1 and 8 of each 21-day 
cycle) in patients with previously treated advanced or metastatic squamous non-small cell 
carcinoma of the lung.  
Safety Lead-In Cohort
Since the combination of LY3023414 and necitumumab will be given for the first time to 
humans, a safety lead-in cohort will be conducted. After at least 6 patients have been treated for 
a full cycle in the lead-in cohort, a Safety Internal Monitoring Committee (SIMC) will conduct a 
review of the safety and available PK data to evaluate the safety and PKs of the combination.  If 
2 (or more) of 3 or 2 (or more) of 6 patients in the lead-in cohort experience DLTs as defined in 
Section 5, 3 to 6 additional patients will be treated at the next lower dose of study drug(s) 
following discussion of the safety data by the SIMC and assessed for DLTs.  If there is a safety 
concern or PK interaction deemed to be clinically significant by the SIMC, the SIMC may 
recommend enrollment of approximately 6 additional patients to further evaluate the safety of 
the combination, or explore other doses of LY3023414 in combination with necitumumab.  In 
the case of unacceptable and/or unmanageable toxicity of the combination at the intended dose 
level the SIMC may decide to discontinue or modify the study (e.g. proceed with a lower dose 
level of study drug(s) tolerated in combination).  All outcomes from these safety reviews will be 
communicated in a timely manner to the participating investigators so that they may notify their 
IRBs.  No amendment will be needed to proceed with a lower dose level of study drug(s).
The SIMC will, at a minimum, be composed of a Sponsor-Assigned Clinical Research Physician, 
Study Chair, Medical Monitor, Sponsor-Assigned Safety Scientist, and Biostatistician.


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A toxicity will be considered dose-limiting, if it occurs within the first cycle of treatment (21
days) to lead-in patients and is deemed at least possibly related to study drug.
Dose-limiting toxicities will be defined as any of the following AEs:

Grade 4 thrombocytopenia; Grade 4 neutropenia ≥7 days; Grade ≥3 febrile neutropenia; 
and Grade ≥3 thrombocytopenia with Grade ≥2 hemorrhage

Grade ≥ 3 non-hematologic toxicity despite maximal medical management with the 
exception of:  

Diarrhea, nausea, or vomiting that resolves to ≤ Grade 2 within 48 hours  

Skin toxicity that resolves to ≤ Grade 2 within 7 days

ALT/AST elevation that resolves to ≤ Grade 2 within 7 days 

Hypomagnesemia that resolves to ≤ Grade 2 within 7 days

Grade 3 mucositis that resolves to ≤ Grade 2 within 7 days.  Grade 4 
mucositis of any duration will be considered a DLT.

Grade 3 fasting hyperglycemia that resolves to ≤ Grade 2 within 7 days.  
Grade 4 hyperglycemia of any duration that results in intensive care unit
admission will be considered a DLT.

Grade 3 fatigue that resolves to ≤ Grade 2 within 5 days. 

Grade 3 hypertension controlled with medical therapy.  

Any lab abnormalities that are not clinically significant and resolve in 72 
hours.

Infusion reactions attributed only to necitumumab

Hy’s law: Hepatocellular injury defined as ALT (or AST) > 3x ULN and total bilirubin > 
2x ULN with no significant cholestasis (ALP< 2x ULN) and no other cause which 
explains the abnormality in liver tests.

Grade >2 skin toxicities despite best supportive care

Unresolved AE that leads to treatment delay of ≥14 days

Any other clinically significant study drug related AE which does not respond to 
supportive care, or is judged to be an unacceptable and/or unmanageable by the 
investigator in collaboration with the Medical Monitor.


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Determination of Dose-Limiting Toxicities
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives at 
least 75% of study drug regimen (LY3023414 and necitumumab) and is observed for at least 21
days following the first dose of study drugs.  Any patients enrolled in the lead-in cohort that do 
not meet the dosing criteria defined above in order to be considered complete will be replaced.  
Post Lead-In Cohort
Following the confirmation of safety for the combination of LY3023414 and necitumumab by 
the SIMC, the study will continue to enroll up to a total of approximately 48 evaluable patients, 
with a planned interim analysis after 24 patients have completed 6 months of follow-up.  The 
interim analysis will be performed purely for the purpose of detecting an efficacy signal, and not 
for the purpose of stopping recruitment.  
Cycles will be 21 days in length.  Patients will be treated until disease progression as defined by 
RECIST v1.1, or any other discontinuation criteria outlined in Section 3.3 as applicable.  Patients 
will be evaluated for response to treatment after every 2 cycles.
As further clinical data become available, this clinical trial may be amended to include the 
addition of other agents to the combination of necitumumab and/or LY3023414.
The Study Schema is presented in Figure 1.


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Figure 1
Study Schema
N = 48
Lead-in cohort includes
6-12 patients
Every Cycle (21 days)
LY3023414 (200mg PO BID continuously) +
necitumumab (800mg IV infusion on Day1 
and Day 8) 
Restaging
Tumor assessments every 2 cycles
Treat until disease progression
or occurrence of unacceptable toxicity
After at least 6 patients have been treated 
for a full cycle in the lead-in portion, a 
Safety Internal Monitoring Committee 
(SIMC) will conduct a review of the safety 
and available PK data.
Follow-Up
Patients who discontinue study treatment prior to the occurrence of disease 
progression will be followed every 3 months (±1 month) from the date of 
last dose of study drug until disease progression or for up to 2 years 
whichever comes first.
After disease progression is documented, patients will be followed every 3 
months (±1 month) for survival (e.g., date and cause of death) for up to 1 
year or death whichever comes first.


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5.1
Treatment Plan
LY3023414
5.1.1
LY3023414 will be self-administered by the patient PO BID on continuous daily dosing.
Patients should take the morning and evening doses of LY3023414 approximately 12 hours apart 
(preferably within a 10- to 14-hour range).  Patients should not consume food for approximately 
1 hour before taking the dose of LY3023414 and should remain in a fasted stated for 1 hour post-
necitumumab infusion.  LY3023414 should be taken with a glass of water at approximately the 
same time each day.  Patients should swallow the capsules as a whole and should not chew or 
crush them.  
If the patient misses a dose of LY3023414, the patient should take the dose as soon as possible, 
but not less than 6 hours before the next dose is due for twice daily dosing.  If the next dose is 
due in less than 6 hours, the patient should skip the missed dose and take the next dose as 
scheduled.
If vomiting occurs after taking LY3023414, the patient should be instructed not to retake the 
dose.  Patients should take the next scheduled dose of LY3023414.  If vomiting persists the 
patient should contact the investigator.
LY3023414 compliance will be assessed by pill counts on Day 1 of each cycle.  The research 
staff will count and document the amount of LY3023414 taken and returned by the patient.  
Necitumumab
5.1.2
All patients will receive 800 mg of necitumumab by IV over 50 minutes on Days 1 and 8 of each 
21-day cycle.  The infusion of necitumumab should start shortly (within 15 min) after the oral 
administration of LY3023414 on days that PKs are being collected. Patients should remain in a 
fasted stated for 1 hour post-necitumumab infusion.
5.1.2.1
Premedication for Necitumumab after Cycle 1
Routine premedication prior to the administration of necitumumab is not mandatory, except in
patients who have experienced a hypersensitivity/infusion-related reaction (IRR) to 
necitumumab.
Patients who have experienced any prior Grade 1-2 hypersensitivity/IRR during the infusion of 
necitumumab should receive premedication with an antihistamine prior to all subsequent 
infusions. After the second occurrence of a Grade 1-2 hypersensitivity/IRR, a corticosteroid and 
an antipyretic (e.g., acetaminophen) should be added to the premedication regimen. Additional 
premedication may be administered at the discretion of the investigator.  For dose reductions and 
more information see Section 6.1.1.
Treatment with skin moisturizers, topical steroids, oral doxycycline, or sunscreen may be
administered as clinically appropriate to patients receiving necitumumab (Mitchell et al. 2008).  
For additional information regarding reactive management of skin toxicity, see Section 6.1.2 for 
more information.


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As with all concomitant medications/procedures, any actions taken to ameliorate skin toxicity
with preemptive medications or procedures will be documented in the concomi tant medication
module of the eCRF.
5.2
Treatment Duration
The end of the study treatment is defined as the date of the last dose of the last patient receiving
study medication.
Patients will be evaluated for toxicity at the start of each cycle.  Every 2 cycles, restaging will 
occur with imaging, laboratory chemistries, and tumor markers as defined in Appendix E
(Schedule of Assessments).  
Patients will be allowed to continue on therapy as long as they do not meet the discontinuation 
criteria listed in Section 3.3, and are considered, by the investigator, to still be receiving clinical 
benefit (patients may continue on therapy after progression criteria have been met only if they 
are considered to be receiving clinical benefit after consulting with the study Medical Monitor 
and depending upon availability of study drug).
5.3
Concomitant Medications
Medications considered necessary for the patient’s safety and well-being may be given at the 
discretion of the investigator with the exception of those listed in Section 5.3.2.  At each visit, 
patients will be asked about any new medications they are taking or have taken after the start of 
the study drug.
Permitted Concomitant Medications
5.3.1
Premedication with anti-emetics is allowed according to standard practice guidelines.
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following:

Bisphosphonate use, as recommended according to practice guidelines

Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor use, as 
recommended according to practice guidelines

Anticoagulation with couma din-derivatives will not be permitted.  However, a maximum 
daily dose of 1 mg will be permitted for port line patency.  Should a thrombotic event 
occur while the patient is receiving treatment the patient may continue, but low molecular 
weight heparin (LMWH) will be the preferred treatment.

Patients who develop hyperglycemia during the study should be treated according to the 
American Diabetes Association guidelines.  It is recommended to start treatment with 
metformin if hyperglycemia occurs.
See Section 5.1.2.1 for additional medications allowed.
Palliative radiation treatment may be allowed after discussion and approval by Medical Monitor.


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Prohibited Concomitant Medications
5.3.2
The following treatments are prohibited while in this study:

No other investigational therapy should be given to patients.  No anticancer agents other 
than the study medications should be given to patients.  If such agents are required for a 
patient, then the patient must first be withdrawn from the study.
Concomitant Medications to be avoided
5.3.3
LY3023414 is a weak inhibitor of CYP3A4 based on in vivo data generated during the DDI arm 
of clinical study CBBA (exposure of probe substrate midazolam increased but the increase was  
less than 2-fold). Therefore drugs that are either sensitive substrates of CYP3A4 or CYP3A4 
substrates with a narrow therapeutic range should be administered with caution in combination 
with LY3023414.
In vitro data showed that the major cytochrome P450 involved in the clearance of LY3023414 
was identified as CYP3A (~80%) and approximately 20% of LY3023414 is metabolized by 
CYP1A2.
Therefore, it is recommended to:
o
Avoid, if possible, strong inhibitors of CYP3A4 and strong and moderate inducers 
of CYP3A4 (Appendix I).
o
Avoid drugs causing QTc interval prolongations (Appendix G, Appendix H).
o
Avoid smoking and record smoking history for all patients.
o
Avoid grapefruit, Seville oranges, or Star fruit.
o
Avoid herbal preparations/medications throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, 
and ginseng.  Patients should stop using these herbal medications 7 days prior to 
first dose of study drug.
5.4
Correlative Studies
Biological samples (i.e., blood and fresh or archival tissue samples, primary or metastatic 
lesions) will be requested and may be analyzed to identify potential biomarkers predictive of 
clinical efficacy of the study drugs and disease progression in this patient population.  The time 
points for the collection of samples for correlative testing are specified in Appendix E.
Tumor biopsy specimens from the primary site or from metastatic lesions from all patients will 
be collected.  Tumor and blood specimens may be tested for biomarkers including, but not 
limited to,
 
.  The 
status of these biomarkers may be analyzed in an attempt to correlate to the clinical patient 
outcome (e.g. 6-month DCR, ORR and PFS).  Blood samples drawn from the patients at 
baseline, Day 1 of Cycle 1 and Cycle 3, and every 2 cycles thereafter, and at the End of 
CCI


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Treatment visit may be assessed to explore potential gene signature(s) for clinical benefit to 
study treatment, such as PI3K/mTOR and EGFR.
Information regarding shipment, handling, and length of retention time, etc. of tissue and blood 
will be provided in the Laboratory Manual.
Samples for Biomarkers
5.4.1
Collection of samples for biomarker research is also part of this study.  Blood and tissue samples 
will be collected.
Samples for biomarker research to be collected from all patients in this study are in Table 1.
Table 1
Biomarker Sample Collection Times 
Sample
Baseline
C1D1 
pre-dose
C3D1
pre-dose
CX*D1 
pre-dose 
End of 
Treatment
Biomarker 
Blood





Tumor 
Tissue** 

* Day 1 of every 2 cycles (C5D1, C7D1, etc.)
** Archival or fresh, primary or metastatic lesions
If a patient has available archived tumor tissue, no pretreatment biopsy is required. If archived 
tissue is not available, a fresh tumor biopsy should be obtained after all other study entry criteria 
have been confirmed, unless in exceptional cases the Medical Monitor and Investigator agree and 
document that the patient may be enrolled without pretreatment tumor tissue.
For patients in the study, a small amount of preserved tumor tissue previously (for example, at 
diagnosis) taken to evaluate the patient’s disease will be required for biomarker research. 
Pretreatment formalin-fixed paraffin-embedded tumor tissue should be in a block, or unstained 
slides. Any block submitted will be returned to the site after sectioning; slides will not be 
returned. 
A tissue biopsy may be taken to provide the required tissue. Details for the handling and 
shipping of the tumor tissue will be provided by the Sponsor in a separate document. The tissue 
samples will be obtained using appropriate method. However, cytological or fine-needle 
aspiration specimens are not acceptable. Due diligence should be used to ensure that tumor 
specimen (not normal adjacent or tumor margins) is provided. Pathology reports accompanying 
the tissue may also be requested. Each sample will be labeled with the patient number and will 
be stored for up to 15 years after the last patient visit at a facility selected by the Sponsor.
Samples may be tested to identify biomarkers predictive of clinical efficacy and disease 
progression as well as to 
 
CCI
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Samples will be stored and analysis may be performed on biomarker variants thought to play a 
role in 
 
 
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 LY3023414 and 
necitumumab.
Samples will be destroyed according to a process consistent with local regulation.
It is possible that biomarker data has already been generated from samples that were collected 
and analyzed prior to enrolling in this trial. This may include data generated from genetic 
analyses. If available, this data may be requested from medical records for use in the research 
described in this section.
5.5
Pharmacokinetic Assessments
Information about LY3023414 PK is available in Section 1.3.3 and in the LY3023414 IB. 
Information about necitumumab PK is available in the necitumumab IB.
 
 
 
LY3023414 PK will be 
investigated at steady state in this study CBBE on Day 8 of Cycle 1 and 3 and Day 1 of Cycle 1, 
2, and 6. A limited PK sampling will be implemented in this study as illustrated in Table 2 and 
Table 3. This sampling scheme aimed at capturing LY3023414 pre-dose and Cmax (LY3023414 
concentrations reach a maximum value at approximately 1 to 2 hours post-dose). The mean half-
life (t½) of LY3023414 is approximately 2 hours (range 1 to 5 hours). Given all this information, 
the proposed sampling scheme in Table 2 and Table 3 is adequate to estimate LY3023414 PK 
using non-linear mixed effect modelling technique.
Necitumumab pharmacokinetics have been investigated across a range of studies in cancer 
patients, and a population PK analysis indicate target mediated drug distribution and a half-life 
of approximately 2 weeks, in accordance with other IgG type mAbs.  Based on the long half-life 
of the drug and the availability of a population PK model, the proposed sampling scheme in 
Table 2 and Table 3 is adequate to estimate necitumumab PK using non-linear mixed effects 
modelling techniques.
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Bio-Analytical Assays for Drug Concentration Measurements 
5.5.1
Pharmacokinetics Samples
LY3023414 concentration will be characterized in whole blood (per the schedule presented in 
Table 2 and Table 3).  Venous blood will be drawn at each time point using a micro sampling 
technique (dried blood spot [DBS] sampling) for quantifying LY3023414 concentration.  In the 
lead-in cohort (i.e. in the initial cohort of 6 and up to 12 patients), classical plasma samples will 
also be drawn to compare LY3023414 plasma concentrations and DBS concentrations.  Detailed 
instructions and supplies for the collection, handling, and shipping of blood and plasma samples 
will be provided by the laboratory manual.  LY3023414 will be assayed using a validated DBS
or plasma liquid chromatography (LC)-mass spectrometry (MS)/MS method.
Necitumumab concentrations will be characterized in serum per the schedule presented in Table
2 and Table 3 Section 5.5 using a validated enzyme-linked immunosorbent assay (ELISA).
A maximum of 5 samples may be collected at additional time points during the study in addition 
to the planned sampling schedule if warranted and agreed upon between both the Investigator 
and Study team.
Bioanalytical samples collected to measure LY3023414 and necitumumab concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.
Samples will be destroyed according to a process consistent with local regulation.
Samples for Immunogenicity Research
5.5.2
Blood samples for immunogenicity testing will be collected to determine antibody production 
against necitumumab.  Immunogenicity will be assessed by a validated assay designed to detect 
anti-drug antibodies in the presence of necitumumab.  Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of necitumumab.  Immunogenicity 
samples will be collected according to the schedule in Table 2 and Table 3.
When any immunogenicity sample is drawn, a sample for drug concentration measurement (PK) 
should also be drawn and analyzed to allow interpretation of immune response.
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.


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Table 2
Pharmacokinetic and Immunogenicity Sample Collection Times for 
Assessment of LY3023414 and Necitumumab Concentration – Lead-In 
Patients
Study Visit
Collection Time (± 15 
minutes)
LY3023414 PK-
DBS/Plasma
Sample
Necitumumab
PK Serum
Sample
Necitumumab
Immunogenicity 
Samplee
Cycle 1 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 1 Day 8
Pre-dose of LY3023414 
and necitumumaba
X
X
Cycle 1 Day 8
At the end of infusion 
(EOI) of necitumumabb
X
X
Cycle 1 Day 8
1 hour post EOIc,d
X
X
Cycle 2 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 3 Day 8
Pre-dose of LY3023414 
and necitumumaba
X
X
Cycle 3 Day 8
At the EOI of 
necitumumabb
X
X
Cycle 3 Day 8
1 hour post EOIc,d
X
X
Cycle 4 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 6 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
End of 
Treatment
~ 30 days post last dose
X
X
X
a: The infusion of necitumumab should start shortly (within 15 min) after the oral administration of LY3023414.
b: This end of necitumumab infusion time point corresponds to approximately 1hour post LY3023414 dose.
c: This time point, 1 hour post end of necitumumab infusion, corresponds to approximately 2 hours post LY3023414 
dose.
d: On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should 
remain in a fasted stated for 1 hour post-necitumumab infusion.
e: In the event of an IRR, sampling as close to the onset of the reaction as possible, at the resolution of the event, and 
30 days following the event.


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Table 3
Pharmacokinetic and Immunogenicity Sample Collection Times for 
Assessment of LY3023414 and Necitumumab Concentration – Post Lead-In 
Patients
Study Visit
Collection Time (± 15 
minutes)
LY3023414 
PK-DBS
Sample
Necitumumab
PK Serum
Sample
Necitumumab
Immunogenicity 
Samplee
Cycle 1 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 1 Day 8
Pre-dose of LY3023414 
and necitumumaba
X
X
Cycle 1 Day 8
At the end of infusion 
(EOI) of necitumumabb
X
X
Cycle 1 Day 8
1 hour post EOIc,d
X
X
Cycle 2 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 3 Day 8
Pre-dose of LY3023414 
and necitumumaba
X
X
Cycle 3 Day 8
At the EOI of 
necitumumabb  
X
X
Cycle 3 Day 8
1 hour post EOIc,d
X
X
Cycle 4 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
X
Cycle 6 Day 1
Pre-dose of LY3023414 
and necitumumaba,d
X
X
End of 
Treatment
~ 30 days post last dose
X
X
X
a: The infusion of necitumumab should start shortly (within 15 min) after the oral administration of LY3023414.
b: This end of necitumumab infusion time point corresponds to approximately 1 hour post LY3023414 dose.
c: This time point, 1 hour post end of necitumumab infusion, corresponds to approximately 2 hours post LY3023414 
dose.
d: On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should 
remain in a fasted stated for 1 hour post-necitumumab infusion.
e: In the event of an IRR, sampling as close to the onset of the reaction as possible, at the resolution of the event, and 
30 days following the event.


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On the days when PK samples are collected, patients will not take the morning LY3023414 dose 
and will not receive their necitumumab infusion until after the pre-dose specimen is obtained.
On the PK days the date and time and amount of the LY3023414 doses associated with the 
LY3023414 PK samples must be recorded in the eCRF.
The date and time of samples collection will be recorded on the requisition form.
Information regarding shipment, handling, and length of retention time, etc. of PK samples will 
be provided in the Laboratory Manual.
5.6
Samples for Pharmacogenomic Research
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, 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 
ethical review boards (ERBs) allow, a blood/saliva sample will be collected for pharmacogenetic 
analysis.  
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 
association with response to LY3023414 and necitumumab.  These investigations may be limited 
to a focused candidate gene study or, if appropriate, genome-wide analysis may be performed to 
identify regions of the genome associated with the variability observed in drug response. The 
pharmacogenetic biomarker 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.
Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor.  The sample and any data 
generated from it can only be linked back to the patient by investigator site personnel.
6.
DOSE MODIFICATIONS
If an AE occurs, the AE will be graded utilizing the NCI CTCAE v 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
and appropriate supportive care treatment will be administered as needed to decrease the signs 
and symptoms thereof.  Dose adjustments will be based on the organ system exhibiting the 
greatest degree of toxicity.
Doses of LY3023414 and necitumumab will be modified based on hematologic and non-
hematologic toxicity.  If dose reductions are necessary, they will be permanent for the remainder 
of the treatment except as noted below in Table 6 for necitumumab due to Grade 3 skin reaction.  
Doses of necitumumab and LY3023414 may be adjusted according to Table 4.  If the responsible 
study drug can be identified, it may be omitted or reduced according to the dose modification 
table and the patient may continue with the other study drug, as appropriate.  For toxicities 
possibly caused by both drugs, both drugs may be omitted or the dose levels of both may be 


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reduced. If the patient is receiving the lowest allowable dose and experiences an AE requiring a 
dose reduction, the offending study drug should be discontinued.  If the offending study drug is 
discontinued, the patient may continue single-agent treatment.  
If any AE occurs, it should resolve to a level that, in the opinion of the investigator, is reasonable 
to allow for continuation of treatment taking into consideration the recommendations below.
If a patient experiences a  Grade 3 drug related AE or an intolerable Grade 2 AE (with the 
exception of skin toxicity, see Table 6), omit dosing of the offending study drug(s) until 
symptoms improve to ≤ Grade 1 or baseline, then resume at a reduced dose of the offending 
study drug(s) according to Table 4. Permanently discontinue study drugs for Grade 4 AEs.  
Grade 3 or 4 laboratory changes that are not clinically significant and which can be corrected 
within 48 hours may not require dose modification.
Re-escalation of study drug(s) may be considered if clinically warranted, following discussion 
and approval by the Medical Monitor.  Re-challenge of patients with dose-reduced study drug(s) 
following recovery from Grade 4 AEs may be considered on a case-by-case basis in consultation 
with the Medical Monitor.  
For specific necitumumab modifications, see section 6.1.
Any patient requiring an AE-related dose delay of more than 21 days after Cycle 1 from the 
intended day of the next scheduled dose due to a study drug related AE should be discontinued 
from the study, unless discussed with the Medical Monitor.
Dose omissions within a cycle do not alter the start of the next scheduled cycle.  Missed doses of 
necitumumab or LY3023414 will not be made up.
A maximum of two dose reductions per drug are allowed in this study.  If more than two dose 
reductions of study drug(s) are necessary for a patient, the responsible agent will be 
discontinued.
Table 4
Dose Level Modifications
Dose Level
LY3023414*
Necitumumab*
Starting Dose 
200 mg PO BID
800 mg IV
Dose Level -1
150 mg PO BID
600 mg IV
Dose Level -2
100 mg PO BID
400 mg IV
*If the responsible study drug can be identified, it may be omitted or reduced according to the dose modification 
table and the patient may continue with the other study drug, as appropriate.  
6.1
Necitumumab Non-Hematologic Toxicities
Dose modifications for non-hematologic toxicities due to necitumumab are summarized below in 
Table 5 and Table 6.
Hypersensitivity/Infusion-Related Reactions
6.1.1
As with other monoclonal ant ibodies, hypersensitivity/IRRs may occur during or following 
necitumumab administration. As a routine precaution each visit, patients treated with 


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necitumumab should be closely monitored for signs and symptoms indicative of a 
hypersensitivity/IRR 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 (epinephrine, 
prednisolone equivalents, etc.) available.
Hypersensitivity/IRRs are defined according to the NCI-CTCAE Version 4.03 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 (Table 5). Additional treatments, chosen according to clinical symptoms and 
institutional standard of care, may be utilized at investigator discretion.


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Table 5
Infusion-Related Reactions – Management Recommendations
Toxicity
First Occurrence 
Second Occurrence
Grade 1

Decrease infusion rate by 50% for the 
duration of the infusion, and monitor 
patient for worsening of conditiona.

For all subsequent infusions, 
premedicate with diphenhydramine 
hydrochloride 50 mg IV (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 conditiona. 

Administer dexamethasone 10 mg IV (or 
equivalent).

For all subsequent infusions, premedicate 
with diphenhydramine hydrochloride 50 
mg IV (or equivalent), acetaminophen 
650 mg orally (or equivalent), and 
dexamethasone 10 mg IV (or equivalent); 
additional premedication may be 
administered at the investigator’s 
discretion.
Grade 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 resumesa.

Monitor patient for worsening of
condition.

If necessary, administer
diphenhydramine hydrochloride 50 
mg IV (or equivalent), 
acetaminophen 650 mg orally for 
fever, and oxygen.

For all subsequent infusions,
premedicate with diphenhydramine
hydrochloride 50 mg IV (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 resumesa.

Administer dexamethasone 10 mg IV (or 
equivalent).

Monitor patient for worsening of
condition.

If necessary, administer diphenhydramine 
hydrochloride 50 mg IV (or equivalent), 
acetaminophen 650 mg orally for fever, 
and oxygen.

For all subsequent infusions, premedicate 
with diphenhydramine hydrochloride 50 
mg IV (or equivalent), acetaminophen 
650 mg orally (or equivalent), and 
dexamethasone 10 mg IV (or equivalent); 
additional premedication may be 
administered at the investigator’s 
discretion.
a Once the infusion rate has been reduced for a Grade 1-2 reaction, it is recommended that the lower rate be utilized 
for all subsequent infusions. The infusion duration should not exceed 2 hours.


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Table 5
Infusion-Related Reactions – Management Recommendations (continued)
Toxicity
First Occurrence 
Second Occurrence
Grade 3-4

Stop the infusion and disconnect the infusion 
tubing from the patient.

Administer diphenhydramine hydrochloride 
50 mg IV (or equivalent), dexamethasone 10 
mg IV (or equivalent), bronchodilators for 
bronchospasm, epinephrine, and other 
medications / treatments as medically
indicated.

Hospital admission may be indicated.

Permanently discontinue necitumumab.

N/A
If a patient should have a hypersensitivity/IRR to necitumumab, all attempts should be made to 
obtain a blood sample for assessment of anti-necitumumab antibody and necitumumab 
concentration as close to the onset of the event as possible, at the resolution of the event, and 
approximately 30 days following the event.
In addition, these same samples may be assessed for PDx markers to provide information on the 
nature of the infusion reaction.
Skin Reactions
6.1.2
If a patient experiences a Grade 1-2 acne-like rash, necitumumab treatment should continue
without dose modification or delay. Reactive treatment recommendations for skin reaction,
based on the Canadian recommendations presented by Melosky et al. 2009 are summarized in
Table 6.
Table 6
Skin Reactions – Management Recommendations
Toxicity
Management Recommendations
Grade 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.
Grade 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.


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Table 6
Skin Reactions – Management Recommendations (continued)
Toxicity
Management Recommendations
Grade 3

Administer topical clindamycin 2% and topical hydrocortisone 1% in lotion 
base twice daily to affected areas until resolution of reaction.

Administer oral minocycline or doxycycline 100 mg twice daily (or 
equivalent), for a minimum of 4 weeks and continuing for as long as rash is 
symptomatic.

Patients are advised to take appropriate protective measures prior to sun 
exposure to avoid exacerbation of rash severity.

Necitumumab administration will be temporarily withheld until symptoms 
resolve to Grade ≤ 2, but not for longer than a maximum of 6 weeks 
following Day 1 of the most recent treatment cycle.

Following improvement to Grade ≤2, necitumumab may be readministered, 
with a dose reduction of 50% (400 mg).  This dose may be increased to 
75% of the original dose (600 mg) after a minimum of one treatment cycle 
(3 weeks), if symptoms do not recur. If symptoms do not recur for another 
treatment cycle, the dose may be re-escalated to the full recommended dose 
(800 mg).

If reactions do not resolve to Grade ≤2 after 6 weeks (that is, after 
withholding 2 consecutive doses of necitumumab), or if reactions recur or 
become intolerable at 50% of the original dose, necitumumab treatment 
should be permanently discontinued.

Patients who experience Grade 3 skin induration/fibrosis will be 
immediately discontinued from necitumumab.
Grade 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.
A dermatology referral may be indicated for skin reactions that do not improve following 1 to 2 
weeks of treatment, reactions that are severely symptomatic (for example, necrosis, blistering, 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 eCRF.
Hypomagnesemia 
6.1.3
Hypomagnesemia has been reported with necitumumab therapy and is considered to be a class
effect with EGFR-targeting antibodies (as with panitumumab and cetuximab). Hypomagnesemia
is reversible following discontinuation of EGFR antibody therapy. Treatment of any
hypomagnesemia should be as clinically indicated according to institutional standard of care, and
necitumumab therapy should be continued unless the investigator has any related safety concern.
Thromboembolic Events
6.1.4
In a randomized Phase III study (INSPIRE) for the combination of necitumumab with 
pemetrexed and cisplatin in non-squamous NSCLC, an increased rate of serious thromboembolic 
events, including fatal events, as compared to the treatment with pemetrexed and cisplatin alone 
has been observed.  In the Phase III study SQUIRE, a higher rate of thromboembolic events 
(e.g., pulmonary embolism, venous thrombosis, cerebral ischemia, peripheral ischemia, 
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.
However, 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 mFOLFOX-6 chemotherapy.
Treatment of any thromboembolic events occurring during necitumumab treatment should be as 
clinically indicated according to institutional standard of care, and the continuation of 
necitumumab therapy in these cases should be decided by the investigator after thorough risk-
benefit assessment for the individual patient.
7.
STUDY ASSESSMENTS AND EVALUATIONS
7.1
Overview
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is shown in Appendix E.  
7.2
Baseline Study Assessments
The physical examination, vital signs, ECOG PS, CBC including differential and platelets, 
fasting CMP, urine dipstick, PT/INR, biomarker blood sample, and HbA1c blood sample should 
be done ≤ 7 days prior to initiation of treatment.  However, if these initi al examinations are 
obtained within 72 hours prior to the initiation of treatment they do not have to be repeated.  
The following information will be collected and procedures will be performed for each patient at 
screening:
≤4 weeks prior to initiation of treatment


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
Written informed consent prior to any other study-related 

Medical history

12-lead ECG performed locally (repeat if clinically indicated)

Concomitant medication review

CT scan of chest 

CT scan of the abdomen and pelvis  

CT/MRI of the brain if a patient has known brain metastases or if clinically indicated

Confirm availability of pretreatment tumor tissue (see Section 5.4).  If archived tissue is 
not available, a fresh tumor biopsy should be obtained after all other study entry criteria 
have been confirmed, unless the Sponsor and Investigator document that the patient may 
be enrolled without pretreatment tumor tissue.
≤7 days prior to initiation of treatment

Physical examination, measurements of height (first visit), weight

Vital signs (resting heart rate, blood pressure [BP], and oral temperature)

ECOG performance status (Appendix A)

Complete blood count (CBC) with 3-part differential and platelets

Fasting comprehensive metabolic profile (CMP) to include: glucose, blood urea nitrogen 
(BUN), creatinine, sodium, potassium, chloride, calcium, carbon dioxide (CO2), alkaline 
phosphatase (ALP), AST, ALT, total bilirubin, total protein, and albumin, phosphorus, 
magnesium, and lactate dehydrogenase (LDH).

PT/INR (repeat if clinically indicated)

HbA1c

Serum or urine pregnancy test (must be performed within 72 hours prior to the initiation 
of treatment)

Urine dipstick

Blood sample for biomarker analysis 
7.3
Study Treatment Assessments
Cycle 1 – Day 1
7.3.1

Physical examination including measurement of weight 

Vital signs (unless collected within the previous 72 hours)

ECOG PS (unless collected within the previous 72 hours [see Appendix A])

12-lead ECG pre-dose


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
AE assessment

Concomitant medication review

CBC, including 3-part differential and platelets (unless collected within the previous 72 
hours) 

Fasting CMP, phosphorus, magnesium and LDH (unless collected within the previous 
72 hours) 

PT/INR (repeat only if abnormal at baseline or if clinically indicated)

Serum or urine pregnancy test (unless collected within 72 hours prior to the initiation of 
treatment)

Urine dipstick (unless collected within the previous 72 hours)

Biomarker blood sample (pre-dose)

PK blood sample ± 15 minutes (pre-dose of LY3023414 and necitumumab[see Table 2
and Table 3])

Immunogenicity blood sample ± 15 minutes (pre-dose of LY3023414 and necitumumab
[see Table 2 and Table 3]).  In the event of an IRR, sampling as close to the onset of the 
reaction as possible, at the resolution of the event, and 30 days following the event.

PGx blood sample (if the sample is not collected Cycle 1 Day 1, it can be collected 
anytime during Cycle 1 or Cycle 2)

Dispense LY3023414. On PK days, pre-dose measurements and dose administration will 
be done in a fasted state.  

Necitumumab IV administration.  Patients should remain in a fasted stated for 1 hour 
post-necitumumab infusion.
Cycle 1 – Day 8
7.3.2

Vital signs 

ECOG PS (see Appendix A)

AE assessment

Concomitant medication review

Study drug compliance assessment

CBC, including 3-part differential and platelets 

Fasting CMP, phosphorus, magnesium and LDH 

Urine dipstick

PK blood sample ± 15 minutes – (pre-dose of LY3023414 and necitumumab, at EOI, and 
1 hour post EOI [see Table 2 and Table 3])  


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
Dispense LY3023414. On PK days, pre-dose measurements and dose administration will 
be done in a fasted state.  

Necitumumab IV administration. Patients should remain in a fasted stated for 1 hour 
post-necitumumab infusion.
Cycle 2 and all Subsequent Cycles – Day 1 (±72 hours)
7.3.3

Physical examination including measurement of weight 

Vital signs 

ECOG PS (see Appendix A)

12-lead ECG pre-dose (Cycles 2, 3, and 4 only)

AE assessment

Concomitant medication review

Study drug compliance assessment

CBC, including 3-part differential and platelets 

Fasting CMP, phosphorus, magnesium and LDH 

PT/INR (repeat only if abnormal at baseline or if clinically indicated)

HbA1c (starting with Cycle 4 Day 1 and every 3 cycles thereafter)

Urine dipstick

Biomarker blood sample (pre-dose of Day 1 Cycle 3 and Day 1 of every 2 cycles 
thereafter)

PK blood sample ± 15 minutes – (pre-dose of LY3023414 and necitumumab, Cycles 2, 4, 
and 6 only [see Table 2 and Table 3])  

Immunogenicity blood sample ± 15 minutes (pre-dose of LY3023414 and necitumumab, 
Cycle 2 Day 1 and Cycle 4 Day 1 only [see Table 2 and Table 3]).  In the event of an 
IRR, sampling as close to the onset of the reaction as possible, at the resolution of the 
event, and 30 days following the event.

Dispense LY3023414.  On PK days, pre-dose measurements and dose administration will 
be done in a fasted state.  

Necitumumab IV administration.  Patients should remain in a fasted stated for 1 hour 
post-necitumumab infusion.
Cycle 2 and all Subsequent Cycles – Day 8
7.3.4

Vital signs 

ECOG PS (see Appendix A)

AE assessment


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
Concomitant medication review

CBC, including 3-part differential, platelets, and hematocrit (Cycle 3 Day 8 only)

PK blood sample ± 15 minutes – (pre-dose of LY3023414 and necitumumab, at EOI, and 
1 hour post EOI, Cycle 3 only [see Table 2 and Table 3])

Dispense LY3023414.  On PK days, pre-dose measurements and dose administration will 
be done in a fasted state.  

Necitumumab IV administration.  Patients should remain in a fasted stated for 1 hour 
post-necitumumab infusion.
7.4
Response Assessment Prior to Cycle 3 and After Every 2 Cycles
Patients will be evaluated radiographically for response to treatment prior to Cycle 3 and after 
every 2 cycles of treatment (i.e. Cycle 5, Cycle 7, etc.).  The following assessments will be 
performed:

CT scans of chest

CT of the abdomen and pelvis

CT/MRI of the brain only if abnormal at baseline
Patients with progressive disease (PD) or unacceptable toxicity should be discontinued from the 
study; patients with stable disease (SD) or response to therapy will continue treatment.
7.5
End of Treatment Visit 
The follow-up evaluations required after treatment ends due to completion of the planned study 
treatment period, disease progression, or once the patient is discontinued due to unacceptable 
toxicity or decision to discontinue treatment by the patient or the study physician are specified in 
Appendix E.
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfil the end of treatment visit.
After withdrawal from or completion of protocol treatment, patients must be followed for AEs 
for 30 calendar days (+ 3 days) after the last dose of study drug.  The following assessments will 
be performed:

Physical examination including measurement of weight

Vital signs

ECOG PS (see Appendix A)

12-lead ECG

AE assessment

Concomitant medication review  

Study drug compliance assessment

CBC, including 3-part differential and platelets  


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
Fasting CMP, phosphorus, magnesium and LDH

HbA1c

Urine dipstick

Blood sample for biomarker analysis

PK blood sample

Immunogenicity blood sample

CT scan chest (does not have to be repeated if done within 8 weeks of End of 
Study Treatment visit )

CT of the  abdomen and pelvis (does not have to be repeated if done within 8 
weeks of End of Study Treatment visit)

CT/MRI of the brain only if abnormal at baseline (does not have to be repeated if 
done within 8 weeks of End of Study Treatment visit)
7.6
Follow-up
Follow-up for Patients Who Discontinue Prior to Disease Progression
7.6.1
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed every 3 months (±1 month) from the date of last dose of study drug until disease 
progression or for up to 2 years whichever comes first.  For ongoing AEs and serious adverse 
events (SAEs) see Section 11.2.1.  Assessments at these visits will be performed as described in 
Appendix E.
Survival Follow-Up
7.6.2
After disease progression is documented, patients will be followed every 3 months (±1 month) 
for survival (e.g., date and cause of death) for up to 2 years or death whichever comes first.  
Patients may be contacted during outpatient visits or by telephone.
8.
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION
8.1
LY3023414
Investigational Product
Dosage Form and Strength
Manufacturer
LY3023414
25 mg, 100 mg, and 200 mg capsules
Eli Lilly and Company
Labeling, Packaging, and Supply
8.1.1
LY3023414 will be supplied as capsules by Eli Lilly and Company.


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At each visit, patients will be dispensed sufficient supplies until the next visit.  Study drug 
compliance will be assessed at each patient visit.  The research staff will count and document the 
amount of LY3023414 taken and returned by the patient.  
The immediate packaging will contain a statement that administration is limited to 
investigational use only.
LY3023414 must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for LY3023414 are included on the investigational product label.
The Sponsor or its representatives must be granted access on reasonable request to check 
LY3023414 storage, dispensing procedures, and accountability records.
If another formulation of LY3023414 becomes available at a later point in time (e.g. tablets), that 
might be used instead of capsules for this study.
Precautions and Risks Associated with LY3023414
8.1.2
Due to the early stage of development, clinical experience with LY3023414 is limited.
Nonclinical toxicology studies identified the GI tract as one of the primary target organs for 
toxicity of LY3023414.  In the ongoing Study CBBA, nausea, vomiting and diarrhea, mostly 
mild-to-moderate in severity, have been reported among the most frequent AEs considered to be 
possibly related to LY3023414.  Patients administered LY3023414 should be monitored for GI 
toxicities and receive supportive treatment as clinically appropriate.  In the ongoing Study 
CBBA, fatigue, mostly mild-to-moderate in severity, has also been reported among the most 
frequent AEs considered to be possibly related to LY3023414.
Hyperglycemia
Nonclinical studies in rats and dogs showed transient, dose-responsive increases in glucose. 
Effects on glucose metabolism are an expected pharmacological effect based on the role that 
PI3K and mTOR pathways play in glucose metabolism.  Dose-related, transient increases in 
glucose (Grade 1-3) and C-peptide levels were noted in patients administered LY3023414 as 
monotherapy.  Patients who develop elevated glucose should be treated according to the 
institutional standard of care.  
QT Interval Prolongation
Nonclinical studies in rats and dogs showed transient, dose-responsive increases in glucose
coinciding with QT interval prolongation.   Inhibition of PI3K/mTOR interferes with the 
metabolic actions of insulin, including glucose transport and glycogen synthesis, resulting in 
increased blood glucose and compensatory release of insulin (and C-peptide) from pancreatic 
cells.  These changes in glucose metabolism might contribute to secondary QT interval 
prolongation.  No clinically relevant QT interval prolongations were identified in patients 
administered LY3023414 as monotherapy.  Patients should be monitored for potential secondary 
prolongation of corrected QT (QTc) intervals by ECG.  Patients should avoid taking concomitant 
medications that are known to induce QTc prolongations as outlined in the protocol (Appendix 
H). 
Please refer to the investigator brochure (IB) for a more thorough discussion.  


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8.2
Necitumumab
Investigational Product
Dosage Form and Strength
Manufacturer
Necitumumab
800 mg/50 mL
Eli Lilly and Company
Labeling, Packaging, and Supply
8.2.1
Necitumumab will also be supplied by Eli Lilly and Company.
All study medications must be kept in a secure place under the storage conditions specified on 
the label.  The expiration date on the label must not be exceeded.
The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records.
Preparation and Administration of Necitumumab
8.2.2
Necitumumab drug product (DP) is compatible with infusion containers composed of polyolefin, 
polyvinyl chloride (PVC), ethylene vinyl acetate and evacuated glass (United States 
Pharmacopeia Type II or local equivalent).  An infusion bag composed of polyolefin, 
polypropylene, and polyethylene prefilled with 0.9% Sodium Chloride Injection, such as 
AVIVA, may also be used.
The following infusion sets have been found to be compatible for necitumumab DP infusion:

A polyethylene-lined PVC infusion set with a 0.22-μm downstream high-pressure, 
protein-sparing in-line filter made of polyethersulfone of 10-cm2 surface area

A PVC (with DEHP) infusion set with a 0.2-μm protein-sparing filter made of 
polyethersulfone of 4.2-cm2 surface area

A polyethylene-lined PVC infusion set with a 0.2-μm protein-sparing in-line filter made 
of polyethersulfone of 10-cm2 surface area

A polyurethane infusion set with a 0.2-μm protein-sparing in-line filter made of 
polyethersulfone of 10-cm2 surface area

A polybutadiene tubing with a 0.2-μm protein-sparing in-line filter made of 
polysulfoneof 9-cm2 surface area
a)
To administer using pre-filled I.V. infusion containers:
Calculate the respective dose and remove the corresponding volume of 0.9% normal 
saline from the prefilled 250 mL container of the correct composition.  Aseptically 
transfer the calculated dose of necitumumab DP to the container to bring the final volume 
in the container back to 250 mL.  Gently invert the container to mix.


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b)
To administer using empty I.V. infusion containers:
Aseptically transfer the calculated dose of necitumumab DP into an empty I.V. container
of the correct composition and add a sufficient quantity of sterile normal saline (0.9% 
weight/volume) to the container to bring the total volume to 250 mL.  Gently invert the 
container to mix.
Only 0.9% normal saline should be used for dilution and post-infusion flushing of infusion line.
Addition of 0.9% normal saline is not required for dose volumes exceeding 250 mL.  Post-
infusion, the infusion line must be flushed with equal to or greater than the hold-up volume of 
the infusion line to ensure delivery of the calculated dose.  Necitumumab should be administered 
as an intravenous infusion over 50 minutes.  The infusion rate must never exceed 25 mg/minute
and consequently necitumumab infusion duration is about 1 hour.  Different lot numbers of 
necitumumab must not be mixed in a single infusion.  The lot number is printed on the container 
label.
Precautions and Risks Associated with Necitumumab
8.2.3
Common risks associated with necitumumab administration are:

Hypersensitivity/IRRs

Skin reactions

Thromboembolic events
Please refer to the necitumumab IB for detailed information on the risks associated with the use 
of necitumumab.
8.3
Accountability for All Study drugs
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
LY3023414 and necitumumab at the site.
All LY3023414 and necitumumab inventories must be made available for inspection by the 
monitor, Sponsor, or representatives of the aforementioned and regulatory agency inspectors 
upon request.
At the end of the study, all approved Drug Accountability Record Form (s) for LY3023414 and 
necitumumab will be completed by the site and sent to the SCRI Innovations Regulatory 
Department.  Study drug supplies must not be destroyed unless prior approval has been granted 
by the Sponsor or its representative.  Disposal of any study drug may occur according to your 
current drug destruction SOP, after review and approval of the SOP by SCRI Innovations.
9.
RESPONSE EVALUATIONS AND MEASUREMENTS
Response and progression will be evaluated in this study using the RECIST v 1.1 (see Appendix 
F).  Lesions are either measurable or non-measurable according to the criteria.  The term 
“evaluable” in reference to measurability will not be used, as it does not provide additional 
meaning or accuracy.


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10.
STATISTICAL CONSIDERATIONS
10.1
Statistical Design
This is a Phase II single-arm, open-label, clinical study of the combination of LY3023414 (200 
mg orally BID) and necitumumab (800 mg administered IV on Day 1 and 8 of each 21-day 
cycle) in patients with previously treated advanced or metastatic squamous non-small cell 
carcinoma of the lung.  
The primary, secondary and exploratory objectives are found in Section 2.
10.2
Sample Size Considerations
 
  Based upon a 1-sided type I error rate of 20% and power 
of 90% the total sample size required to test the null hypothesis is 48 evaluable patients. A 
planned interim analysis will take place when 24 patients are evaluable for the primary endpoint, 
including the initial 6 patients treated at that dose to establish the safety and pharmacokinetics of 
the combination. The O’Brien Fleming alpha spending function is 0.067 at the interim analysis 
and 0.131 at the final analysis. 
 
  
The sample size is calculated using EAST.
10.3
Analysis Population
The following analysis populations will be used:

All enrolled patients who have received at least one dose of study medication will 
comprise the Full Analysis Set (FAS).  This population will be used for the safety
analysis and the primary analyses of the efficacy endpoints.
10.4
Data Analysis
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented. A SAP outlining methods for analysis and data display will be 
developed and approved prior to database lock.  Any deviation(s) from the approved plan or ad-
hoc evaluations or analyses will be properly documented in the clinical study report.
Demographics and Baseline Characteristics
10.4.1
Demographic and baseline disease characteristics will be summarized.  Data to be tabulated will 
include demographic features such as age, sex and race, as well as disease-specific 
characteristics.
The number and percentages of patients screened, treated, completed the treatment/study and 
withdrawn from treatment/study for any reasons will be presented.
Efficacy Analysis
10.4.2
All efficacy analyses will be performed using the FAS.
CCI
CCI


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RECIST v 1.1 will be used to assess tumor response.  Tumors will be assessed at screening, after 
every 3 cycles, and at follow-up visits.  Reassessment of tumors will be done by the same 
methods used to establish baseline tumor measurements.  All responding patients (CR and PR) 
must have their response confirmed no less than 4 weeks after the first documentation of 
response.  For SD, follow-up measurements must meet the SD criteria at least 9 weeks after 
study entry.  
10.4.2.1
Primary Endpoint
6-Month Disease Control Rate
The 6-month DCR is defined as the number of patients with PFS > 6 months (or 26 weeks, to 
accommodate the scheduled tumor assessment at week 24 be delayed by up to 2 weeks) divided 
by number of patients with baseline tumor assessment .
The primary endpoint, 6-month DCR, will be presented as the point estimate with its associated 
95% Clopper-Pearson confidence interval (CI).  
10.4.2.2
Secondary Endpoints
Overall Response Rate (ORR)
The ORR based on each patient’s best objective response will be determined for all patients 
evaluable via the RECIST v 1.1 criteria.  The ORR (%) will be calculated as the number of 
patients with best objective response of CR or PR divided by the number of patients with 
measurable disease at baseline.  The best objective response for a given patient will be based on 
objective responses determined from data obtained up to: progression, the last evaluable 
assessment in the absence of progression, or initiation of subsequent anticancer therapy.  Patients 
for whom an objective response cannot be determined or for who the best objective response is 
NE will be considered non-responders.  The ORR will be summarized along with the 95% 
Clopper Pearson CI. 
Disease Control Rate
DCR is defined as number of patients with CR, PR, or SD as the best objective response divided 
by number of patients with baseline tumor assessment.  
Progression–free survival (PFS)
PFS is defined as the time from enrollment until the date of disease progression per RECIST or 
death by any cause. Patients who have not progressed or died at the time of assessment will be 
censored at the time of the last date of tumor assessment.  Patients who are enrolled but do not 
receive treatment and patients who have no evaluable visits will be censored on day 1.  Patients 
who received new anti-cancer therapy before disease progression or death will be censored to the 
last tumor assessment date prior to the new anti-cancer therapy. PFS will also be analyzed by 
including the clinical progression date as sensitivity analysis. Detailed derivation rules will be 
specified in the SAP.


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Overall survival (OS)
OS is defined as the time from enrollment until the date of death by any cause. Patients who lost 
follow up or did not die at the time of assessment will be censored at the time of the last known 
alive date.  Detailed derivation rules will be specified in the Statistical Analysis Plan.
10.4.2.3
Exploratory Endpoints
Exploratory analyses including, but not limited to, according to biomarker status of EGFR and 
PI3K/mTOR signalling alterations may be performed as deemed appropriate.
10.4.2.4
Subgroup Analyses
For exploratory purposes, efficacy sub-group analyses may also be performed if applicable, 
using the FAS.  The details of these analyses and selection of the prognostic factors and/or 
baseline characteristics will be specified in the SAP.
For ORR, the estimates and the associated 95% CI (based on the Clopper-Pearson method) in 
each sub-group will be calculated. 
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and the 
associated 95% CI will be provided.
Safety Analysis
10.4.3
The NCI CTCAE v 4.03 will be used to grade all AEs (severity grade).  A copy of the CTCAE 
scoring system may be downloaded from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
Duration and treatment of toxicities will be recorded.  The safety measures will be assessed on 
an ongoing basis.  The safety variables will be assessed by body system.  Any AEs that are 
considered probably or possibly study drug-related will be monitored until resolution or 
stabilization.
Toxicity profile data will include AEs and laboratory parameters.  Safety data will be tabulated 
for all patients.  Adverse terms recorded on the eCRFs will be standardized using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Treatment -emergent AEs (TEAEs) defined as 
events that start or worsen after the first dose of study treatment, will be summarized and 
tabulated in accordance with system organ class (SOC) and preferred term by overall incidence, 
severity, and relationship to study treatment.  The tabulation of laboratory parameters will 
indicate the normal range of each parameter.  Each value will be classified according to CTCAE 
v 4.03 where applicable.
Other safety endpoints, including laboratory results, vital signs and ECG findings, will be 
summarized for all patients in the Safety Analysis Set. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized.


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Pharmacokinetics
10.4.4
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug(s) and have had sufficient post-dose samples collected to allow estimation of PK 
parameters.  Blood (all patients) and plasma (initial lead-in cohort only, 6 to 12 patients)
concentrations of LY3023414 and serum concentration for necitumumab will be used to 
calculate LY3023414 and necitumumab PK parameters, respectively.  Based on the limited 
sampling scheme the primary LY3023414 and necitumumab PK parameters will be Cmax and
Cmin of LY3023414 and necitumumab following multiple doses. 
Pharmacokinetic parameters will be listed by individual patient and summarized by descriptive 
statistics (means, medians, ranges, standard deviations and coefficient of variation and, as 
appropriate, by dose levels.
Other parameters, such as t1/2, CLss/F, and Vss/F may be reported through analysis of the data 
using nonlinear mixed effect modeling (NLME) techniques.  Additional exploratory analyses 
will be performed if warranted by data and other validated PK software programs 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. 
Further details on the PK analysis will be documented in a separate PK analysis plan.
10.5
Analysis Time Point
Final Analysis
10.5.1
The final analysis of the study will occur when all patients have either finished month 6 tumor 
assessment or discontinued from the study medication.
Planned Interim Analysis
10.5.2
Interim analysis will be conducted when a total of 24 patients have had month 6 tumor 
assessment.  A 6-month DCR rate of 44% will be used as the boundary to access the efficacy 
during the interim analysis.  A 6-month DCR rate of 36% will be used as the boundary to assess
the efficacy of LY3023414 and necitumumab in the final analysis.
The results from the interim analyses will be examined by a committee that will be established 
prior to the inclusion of the first patient in the trial.  The committee will consist of at least a Lilly 
medical director, a Lilly clinical research physician/clinical research scientist, and a Lilly 
statistician and will make recommendations about the trial.  The outcome of the interim analyses 
will be documented, and a written letter will be submitted to the IRB(s) and the investigators for 
documentation purposes. Enrollment will continue while the interim analysis is being 
performed.
Safety Review
10.5.3
After at least 6 patients in the lead-in cohort have been treated for a full cycle, a SIMC will 
review the safety and PK data.  If 2 (or more) of 3 or 2 (or more) of 6 patients in the lead-in 
cohort experience DLTs as defined in Section 5, 3 to 6 additional patients will be treated at a
lower dose of study drug(s) following discussion of the safety data by the SIMC and assessed 


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for DLTs.  If there is a safety concern or PK interaction seen deemed to be clinically significant 
by the SIMC, the SIMC may recommend enrolling approximately 6 additional patients to further 
evaluate the safety of the combination, or explore other dose combinations to assure safety at a 
maximal exposure of study drug.  In the case of unacceptable and/or unmanageable toxicity of 
the combination at the intended dose level the SIMC may decide to discontinue or modify the 
study (e.g. proceed with a lower dose level of study drug(s) tolerated in combination).  Any 
outcome of these safety reviews will be communicated in a timely manner to the participating 
investigators so that they may notify their IRBs.  No amendment will be needed to proceed with 
a lower dose level of study drug(s).  
Safety will be monitored as defined by the medical monitoring plan.  The safety profile will be 
reviewed by the Medical Monitor and Sponsor Designees.
The SIMC will, at a minimum, be composed of a Sponsor-Assigned Clinical Research Physician, 
Study Chair, Medical Monitor, Sponsor-Assigned Safety Scientist, and Biostatistician.
The criteria for assessing safety in these patients are found in Section 5.
11.
SAFETY REPORTING AND ANALYSES 
Investigators are responsible for monitoring the safety of patients who have entered into 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 the patient during the study.
The investigator remains responsible for following, through an appropriate health care option, all 
AEs that are serious or that caused the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved, the event is no longer considered to be 
drug-related, the event becomes stable or returns to baseline, a new treatment is initiated for the 
patient, or the patient dies or is lost to follow-up.  Frequency of AE and SAE follow-up 
evaluation is left to the discretion of the investigator.
Investigators or their designees must document their review of each laboratory report.
11.1
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 occurrence 
in a patient or clinical investigation patient administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
ECGs, vital sign measurements, and so on, that occur should also be reported to Lilly or its 
designee as an AE using the same guidelines and schedules as those for AEs.  Lack of drug 
effect is not an AE in clinical studies because the purpose of the clinical study is to establish drug 
effect.


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The investigator, monitor, and Sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE Version 4.03.
The CTCAE Version 4.03 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 CTCAE Version 4.03 criteria, the investigator will be 
responsible for selecting the appropriate SOC and assessing severity grade based on the intensity 
of the event.  Note that both CTCAE term (actual or coded) and severity grade must be selected 
by study site personnel and collected on the eCRF.  This collection is in addition to verbatim text 
used to describe the AE.  
Minor updates to the CTCAE Version 4.03 from the NCI will not necessitate a protocol 
amendment, and the use of updated CTCAE Version 4.0 will not be considered a protocol 
violation.  
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the Sponsor or designee to corresponding terminology 
within MedDRA.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding should be collected, if feasible, for regulatory 
reporting and drug safety evaluation.  
For all enrolled patients, 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.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  All AEs 
related to protocol procedures are reported to Lilly or designee.
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 the circumstances and data leading to any 
such dosage reduction or discontinuation of treatment.  This information must also be 
documented in the eCRF.
The investigator decides whether he or she interprets the observed safety signals as either related 
to disease, to the study medication, study procedure, or other concomitant treatment or 
pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible.

Does not know:  the investigator cannot determine.


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
Not related:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures, all “probably related,” “possibly related,” or “does 
not know” AEs and SAEs will be defined as related to study drug.
11.2
Serious Adverse Events
Previously planned (that is, prior to signing the informed consent form [ICF]) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened during the course 
of the study.
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precip itating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs.
An SAE is any AE during this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

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 SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  
Serious AEs due to disease progression, including death, should not be reported unless the 
investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Sponsor-approved method.  Alerts issued via telephone are to be 
immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
If an investigator becomes aware of SAEs occurring after the patient’s participation in the study 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the Sponsor, and the SAEs will be entered in the 
Lilly Safety System.


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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 study may be 
found in the IB.
Adverse Event and Serious Adverse Event Reporting
11.2.1
Prior to Administration of Study Drug(s)
Although all AEs after signing the ICF are recorded in the CRF, SAE reporting begins after the 
patient has signed the ICF and has received study treatment.  However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedures.
On Study
All AEs and SAEs, regardless of relatedness to study drug, or protocol procedures, occurring 
while the patient is receiving study drug(s) must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study 
drug(s) to when he/she receives the last dose of study drug(s).
Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug, or protocol procedures, occurring 
during the Follow-Up Visit must be reported to Lilly or its designee.  The Follow-Up Visit starts 
the day after the last dose of study drug.  At the end of the Follow -Up Visit, the patient will be 
required to have specific safety assessments according to the Study Schedule (Appendix E).  The 
timing of these safety assessments is 30 days ± 3 days after the last dose of study drug.
Following the safety assessments, which mark the end of the Follow -Up Visit, the patient will be 
discontinued from the study.  If there is an ongoing AE or SAE that is possibly related to study 
drug the investigator remains responsible for following, through an appropriate health care 
option, AEs that are serious, considered related to the study, o r 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.
After the Follow-Up Visit, only new AEs or SAEs that are considered possibly related to study 
drug or protocol procedures should be reported to Lilly or their designee.
To report an SAE, the Lilly SAE Report Form should be completed with the necessary 
information.
The SAE report should be sent to Lilly via fax using the following contact information (during 
both business and non-business hours):
Lilly Safety Department
Safety Dept. Fax #:      
Transmission of the SAE report should be confirmed by the site personnel submitting the report.
PPD


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Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to Lilly as soon as it is available; these reports should be submitted using the 
Lilly SAE Report Form.  The detailed SAE reporting process will be provided to the sites in the 
SAE reporting guidelines contained in the Study Reference Manual.
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB.
11.3
Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Complaints related to unblinded concomitant drugs are reported directly to the manufacturers of 
those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
12.
QUALITY ASSURANCE AND QUALITY CONTROL
12.1
Monitoring
Site monitoring shall be conducted to ensure that patient protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, GCP/ICH and, when appropriate, regulatory guidelines.
12.2
Audits and Inspections
The investigator will permit study-related quality audits and inspections by the Sponsor or its 
representative(s), government regulatory authorities, and the IRB of all study-related documents 
(e.g., source documents, regulatory documents, data collection instruments, case report forms).  
The investigator will ensure the capability for review of applicable study-related facilities.  The 
investigator will ensure that the auditor or inspector or any other compliance or QA reviewer is 
given access to all study-related documents and study-related facilities.
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB, the Sponsor or its representative(s).


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13.
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS
This research study will be conducted according to the standards of Good Clinical Practice 
outlined in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government 
regulations, institutional research policies and procedures and any other local applicable 
regulatory requirement(s).
13.1
Institutional Review Board Approval
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (i.e., 
Principal Investigator payments) and compensation available to the patients and documentation 
evidencing the Principal Investigator’s qualifications should be submitted to the IRB for ethical 
review and approval if required by local regulations, prior to the study start.
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  Investigators 
will be advised by the Sponsor or designee whether an amendment is considered substantial or 
non-substantial and whether it requires submission for approval or notification only to an IRB.
Safety updates for LY3023414 and necitumumab will be prepared by the Sponsor or its 
representative as required, for distribution to the investigator(s) and submission to the relevant 
IRB.
13.2
Regulatory Approval
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities.
13.3
Informed Consent
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF.
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
relevant regulatory authorities, as well as local county authority o r state regulations and national 
requirements.
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 


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obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the investigator to the patient.
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained.
Confidentiality
13.3.1
13.3.1.1
Patient Confidentiality
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws

The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study

Whether the authorization contains an expiration date

The rights of a research patient to revoke his or her authorization
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period.
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representat ives of Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data. 
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF database system.  No material bearing a 
patient’s name will be kept on file by Sponsor.  Patients will be informed of their rights within 
the ICF.


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13.3.1.2
Investigator and Staff Information
Personal data of the investigators and sub-investigators may be included in the Sponsor or the 
SCRI Innovations database, and shall be treated in compliance with all applicable laws and 
regulations.  When archiving or processing personal data pertaining to the investigator or sub 
investigator, the Sponsor and/or SCRI Innovations shall take all appropriate measures to 
safeguard and prevent access to this data by any unauthorized party.
13.4
Financial Information
The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided and retained.
14.
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY
14.1
Amendments to the Protocol
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation.
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of the 
Sponsor and the Principal Investigator supporting the study.  The written amendment must be 
reviewed and approved by the Sponsor, and submitted to the IRB at the investigator’s facility for 
the board’s approval.
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility.
The amendment will be submitted formally to the relevant regulatory authorities by the Sponsor 
as applicable, and IRB approved obtained specifically when an increase to dosing or patient 
exposure and/or patient number has been proposed; or, when the addition or removal of an 
Investigator is necessitated.
Items requiring a protocol amendment with IRB and if necessary other relevant regulatory 
authorities approval may include but are not limited to, the following:

Change to study design

Risk to patient

Increase to dose or patient exposure to drug

Patient number increase

Addition or removal of tests and / or procedures

Addition/removal of a Study Chair


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It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained.
14.2
Documentation Required to Initiate the Study
Before the study may begin in the United States (US) certain documentation required by FDA 
regulations and ICH GCP must be provided by the Investigator.  The required documentation 
should be submitted to:
SCRI Innovations
3322 West End Avenue, Suite 900
Nashville, TN  37203
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following:

A signature-authorized protocol and contract

A copy of the official IRB approval of the study and the IRB members list

Current Curricula Vitae for the principal investigator and any associate investigator(s) 
who will be involved in the study

Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory

Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed

A copy of the IRB -approved consent form  containing permission for audit by 
representatives of  SCRI Innovations, the Sponsor, the IRB, and the FDA

Financial disclosure forms for all investigators listed on Form FDA 1572 (if applicable, 
i.e., for covered trials)

Site qualification reports, where applicable

Verification of Principal Investigator acceptability from local and/or national debarment 
list(s) 
14.3
Study Documentation and Storage
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate.
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 


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laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence.
The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed eCRFs on a compact disc, IRB approval documents, Financial 
Disclosure forms, patient identification lists, enrollment logs, delegation of authority log, staff 
qualification documents, laboratory normal ranges, records relating to the study drug including 
accountability records.  Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition.  Each form of drug accountability record, at a 
minimum, should contain Principal Investigator name, date drug shipped/received, date, quantity 
and batch/code, or lot number for identity of each shipment.  In addition, all original source 
documents supporting entries in the eCRF must be maintained and be readily available.
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation.
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR Part 
56.115 for at least 3 years after completion of the research.
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment / delivery of the 
drug for investigational use is discontinued and FDA has been notified that the investigation has 
been discontinued.
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs and medical records), all 
original, signed ICFs, and copies of all eCRFs, records, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  Sponsor or its representatives will notify the 
investigator(s)/institutions(s) when the study-related records are no longer required.


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If the investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor 
and its representative should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
investigator must obtain the Sponsor’s written permission before disposing of any records, even 
if retention requirements have been met.  All study files will be maintained by the Sponsor or its 
representative throughout the study.  If study files are maintained by a representative of the 
Sponsor, the study files will be transferred to the Sponsor at the conclusion of the study.
14.4
Data Collection
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study.
In order to maintain confidentiality, only study number, patient number, initials and date of birth 
will identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to SCRI 
Innovations and replaced instead with the patient number and patient’s initials.  The investigator 
will maintain a personal patient identification list (patient numbers with corresponding patient 
identifiers) to enable records to be identified and verified as authentic.  Patient data/information 
will be kept confidential, and will be managed according to applicable local, state, and federal 
regulations.
All data requested by the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided.
The investigator will electronically sign and date the patient eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the 
Principal Investigator, once all data for that patient is final.
14.5
Disclosure and Publication Policy
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study may be 
published and/or presented as per the Sponsor’s disclosure process.
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The investigator acknowledges that the study 
is part of a multi-center study and agrees that any publication by the investigator of the results of 
the study conducted at research site shall not be made before the first multi-center publication.  
In the event there is no multi-center publication within fifteen (15) months after the study has 
been completed or terminated at all study sites, and all data has been received, the investigator 
shall have the right to publish its results from the study, subject to the notice requirements 


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described herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator 
shall provide the Sponsor thirty (30) days to review a manuscript or any poster presentation, 
abstract or other written or oral material which describes the results of the study for the purpose 
only of determining if any confidential or patentable information is disc losed thereby.  If the 
Sponsor requests in writing, the investigator shall withhold any publication or presentation an 
additional sixty (60) days solely to permit the Sponsor to seek patent protection and to remove 
any SCRI Innovations Confidential Information from all publications.


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15.
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American Society of Clinical Oncology Guidelines 2014
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Kim CH. Druggable Targets of Squamous Cell Lung Cancer. Turberc Respir Dis. 2013:75:231-
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Kris MG, Johnson BE, Berry LD, et al. Using Multiplexed Assays of Oncogenic Drivers in Lung 
Cancers to Select Targeted Drugs. JAMA. 2014:311(19): 1998-2006. 
Kuenen et al. 2010
Kuenen B, Witteveen PO, Ruijter R, et al. A phase I pharmacologic study of necitumumab 
(IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with
advanced solid malignancies [published correction appears in Clin Cancer Res.
2010;16(18):4681]. Clin Cancer Res. 2010;16(6):1915-1923.
Kwak et al. 2010
Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic Lymphoma Kinase Inhibition in Non–
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Maemondo et al. 2010
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or Chemotherapy for Non–Small-Cell 
Lung Cancer with Mutated EGFR. NEJM 2010:362:2380-2388.
Melosky et al. 2009
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during EGFR-targeted monoclonal antibody treatment for gastrointestinal malignancies:
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Mitsudomi et al. 2010
Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with 
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16.
APPENDICES
Appendix A: ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity. Fully active, able to carry on 
all pre-disease performance without 
restriction.
100
Normal, no complaints, no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, 
office work).
80
Normal activity with effort; some signs or 
symptoms of disease.
70
Cares for self, unable to carry on normal 
activity or to do active work.
2
In bed < 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours.
60
Requires occasional assistance, but is able to 
care for most of his/her needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed > 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
40
Disabled, requires special care and 
assistance
30
Severely disabled, hospitalization indicated.  
Death no imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
20
Very sick, hospitalization indicated.  Death 
not imminent.
10
Moribund, fatal processes progressing 
rapidly.
5
Dead
0
Dead


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Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease.
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256.


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Appendix C: Canadian Cardiovascular Society (CCS) Angina Grading Scale
The following table presents the CCS classification of cardiac disease.
Grade
Description
I
Ordinary physical activity does not cause angina, such as walking and climbing stairs. 
Angina with strenuous or rapid or prolonged exertion at work or recreation.
II
Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking 
uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional 
stress, or only during the few hours after awakening. Walking more than two blocks 
on the level and climbing more than one flight of ordinary stairs at a normal pace and 
in normal conditions
III
Marked limitation of ordinary physical activity. Walking one or two blocks on the 
level and climbing one flight of stairs in normal conditions and at normal pace
IV
Inability to carry on any physical activity without discomfort, anginal syndrome may 
be present at rest
References:  Campeau Lucien. Grading of angina pectoris. Circulation 1976;54:5223
Available on the Canadian Cardiovascular Society Website at www.ccs.ca


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Appendix D: Guidelines for Women of Childbearing Potential and Fertile Male Patients
Acceptable Contraception Methods:  
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 6 months after 
stopping treatment.  Women must not breast-feed for 4 months after stopping treatment.
Highly effective contraception is defined as either:
True Abstinence
When this is in line with the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception.
Sterilization
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to study entry.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment.
Male Partner Sterilization
When the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate.
Use of a combination of any two of the following (one from a + one from b):
a)  Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b)  Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository.
Fertile male patients, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus spermicidal agent during the 
study treatment period and for 6 months after the last dose of study drug, and should not father a 
child during this period.
Male patients must also refrain from donating sperm during their participation in the study.
Unacceptable Contraception Methods: for women of childbearing potential include:

IUD progesterone T

Female condom

Natural family planning (rhythm method) or breastfeeding

Fertility awareness

Withdrawal

Cervical shield


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Pregnancies
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to the 
SCRI-Innovations Safety Department within 24 hours of learning of its occurrence.  The 
pregnancy should be followed up for 3 months after the termination of the pregnancy to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the Sponsor.  Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study drug of any pregnancy 
outcome.  Any SAE experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
drug(s) in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother.
Women Not of Childbearing Potential are defined as Follows:  

Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms). 

Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy).  

Women who are > 45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 12 months OR who have a follicle 
stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL 
(140 pmol/L).

Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH > 40 mIU/mL and estradiol < 40 pg/mL prior to 
initiation of hormone-replacement therapy.


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Appendix E: Schedule of Assessments
Assessments
Screening
Study Treatment
Off-Treatment
Follow-Up
Cycle 1
Cycle 2 & All 
Subsequent Cycles
(±72 hrs)
Response Assessments 
Prior to Cycle 3 & 
every 2nd Cycle 
thereafter (i.e. 5, 7, etc.)
End of Study 
Treatmentp
(+3 days)
Off Treatment 
Prior to 
Progressionq
(±1 month)
Survivalr
(±1 
month)
Baselinea
D1
D8
D1
D8
TESTS AND OBSERVATIONS
Informed consent
X
Medical history
X
Physical examb 
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
ECOG PS 
X 
X
X
X
X
X
X
12-lead ECGd
X
X
Xd
X
Adverse event evaluation
X
X
X 
X
X
Concomitant medication review
X
X
X
X
X
X
Study drug compliance 
X
X
X
Survival status
X
STUDY TREATMENT
LY3023414 PO BID (continuous 
dosing)k
X
X
X
X
Necitumumab IVk
X
X
X
X
LABORATORY EVALUATIONS
CBC, 3-part differential, and 
platelets
X
X
X
X 
Xs
X
Fasting CMPe, phosphorus,
magnesium and LDH
X
X
X
X
X
PT/INRf
X
Xf
Xf
Serum or urine pregnancy testg
Xg
Xg
Urine dipstick
X
X
X
X
X
Biomarker blood sampleh
Xh
Xh
Xh
X
HbA1c blood samplei
X
Xi
Xi
PK blood samplej,k
Xj,k
Xj,k
Xj,k
Xj,k
Xj
Immunogenicity blood samplel
Xl
Xl
Xl


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Appendix E: Schedule of Assessments
Assessments  
Screening
Study Treatment
Off-
Treatment
Follow-Up
Cycle 1
Cycle 2 & All 
Subsequent Cycles
(±72 hrs)
Response Assessments 
Prior to Cycle 3 & every 
2nd Cycle thereafter (i.e. 
5, 7, etc.) 
End of 
Study 
Treatmentp
(+3 days)
Off 
Treatment 
Prior to 
Progressionq
(±1 month)
Survivalr
(±1 month)
Baselinea
D1
D8
D1
D8
LABORATORY EVALUATIONS
PGx blood samplet
X
Archived or fresh tumor tissuem
Xm
STAGING
CT scan of chest, abdomen and 
pelvisn
Xn
Xn
Xn
Xn
CT/MRI of the braino
Xo
Xo
Xo
Xo
a
The physical examination, vital signs, ECOG PS, CBC including differential and platelets, fasting CMP, urine dipstick, PT/INR, biomarker blood sample, and HbA1c blood sample should 
be done ≤7 days prior to initiation of treatment.  However, if these initial examinations are obtained within 72 hours prior to the initiation of treatment they do not have to be repeated.  The 
ICF, medical history, concomitant medications review, 12-lead ECG, scans to document evaluable disease (i.e., tumor measurement) and archived or fresh tumor tissue should be collected
≤4 weeks prior to initiation of treatment.     
b
Physical examination will include measurements of height and weight at the baseline visit.  Physical examinations (PE) done at all other times during the study will include only weight.  
c
Vital signs include resting heart rate, blood pressure, oral temperature
d
ECG performed locally at baseline, pre-dose on Cycles 1 -4, and at the End of Treatment visit.  Repeat if clinically indicated.
e
Fasting CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, albumin, phosphorus,
magnesium and LDH.  
f
PT/INR will only need to be repeated if abnormal at baseline or if clinically indicated.  Patients requiring the initiation of an anti-coagulation therapy during study treatment should have 
their coagulation test performed on a weekly basis.
g
Pregnancy tests will only be performed in women of childbearing potential ≤72 hours prior to first dose of study treatment.
h
Biomarker blood samples will be taken at baseline and pre-dose on Day 1 of Cycles 1 and 3, and every 2 cycles thereafter, and at the End of Treatment visit.
i
HbA1c blood sample will be taken at baseline, on Day 1 of Cycle 4 and every 3 cycles thereafter, and at the End of Treatment visit..    
j
PK blood samples will have a window of ± 15 minutes.  PK blood samples on Cycle 1 and Cycle 3 Day 8 are pre-dose of LY3023414 and necitumumab, at EOI, and 1 hour post EOI (see 
Table 2 and Table 3).  PK blood samples for Cycles 2, 4, and 6 Day 1 are pre-dose of LY3023414 and necitumumab (see Table 2 and Table 3).  A PK sample will be taken at the End of 
Treatment visit.  
k
On PK days, pre-dose measurements and dose administration will be done in a fasted state.  Patients should remain in a fasted stated for 1 hour post-necitumumab infusion.


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Appendix E: Schedule of Assessments
l
Immunogenicity blood samples will have a window of ± 15 minutes.  Immunogenicity blood samples on Cycles 1, 2, and 4 Day 1 are pre-dose of LY3023414 and necitumumab (see Table 2 
and Table 3).  An immunogenicity sample will be taken at the End of Treatment visit.  In the event of an IRR, sampling as close to the onset of the reaction as possible, at the resolution of 
the event, and 30 days following the event.
m
Confirm availability of pretreatment tumor tissue (see Section 5.4).  If archived tissue is not available, a fresh tumor biopsy should be obtained after all other study entry criteria have been 
confirmed, unless the Sponsor and Investigator document that the patient may be enrolled without pretreatment tumor tissue.
n
CT scans of the chest, abdomen and pelvis ≤4 weeks prior to initiation of treatment.  CT scans should be taken prior to Cycle 3 and after every 2 cycles of treatment thereafter, and at the End 
of Study visit (if scans were not taken in the previous 8 weeks).  
o
CT/MRI of the brain at baseline if a patient has known brain metastases or if clinically indicated.  If abnormal at baseline, repeat prior to Cycle 3 and after every 2 cycles of treatment 
thereafter, and at the End of Study visit (if scans were not taken in the previous 8 weeks).
p
After patients complete therapy or are discontinued from treatment they will visit the study center within 30 days (+3) after finishing treatment for end of treatment assessments.  Patients 
must be followed for AEs for 30 calendar days after the last dose of study drug.  For ongoing AEs and serious adverse events (SAEs) see Section 11.2.1.  
q
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 3 months (±1 month) from the date of last dose of study drug until disease 
progression or for up to 2 years whichever comes first.  
r
After disease progression is documented, patients will be followed every 3 months (±1 month) for survival (e.g., date and cause of death) for up to 2 years or death whichever comes first.  
Patients may be contacted during outpatient visits or by telephone.
s
Cycle 3 only.
t
If the PGx blood sample is not collected Cycle 1 Day 1, it can be collected anytime during Cycle 1 or Cycle 2


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Appendix F: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Patients with Measurable Disease
Patients with measurable disease will be evaluated for response using the RECIST v 1.1 
(Eisenhauer et al. 2009).  Lesions are either measurable or non-measurable using the criteria 
provided below.  The term “evaluable” in reference to measurability will not be used, as it does 
not provide additional meaning or accuracy.
Baseline Eligibility
Measurable Disease:
Tumor lesions: Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of:

10 mm by CT by computerized tomography (CT scan slice thickness 
no greater than 5 mm).

10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-
measurable).

20 mm by chest x-ray.
Skin lesions:  Documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.
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.  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-Measurable Disease:
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 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses, 
abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
Target Lesions:
The most reproducible measurable lesions, up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs should be 
identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), should be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible repeated 
measurements.  Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a short axis of 
≥15 mm by CT scan.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then as noted 
above, only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
response.


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Appendix F: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Non-Target Lesions:
All other lesions should be identified as non-target lesions at baseline.  
Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.
Guidelines for Evaluation of Measureable Disease
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment, as per protocol screening 
requirements.
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 preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a treatment.
Clinical Lesions:
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter.  In the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.
Chest X-ray:
Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, a CT scan is 
preferable.
Conventional CT and MRI:
CT, MRI:  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less.  When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans). 
Ultrasound:
When the primary trial endpoint is objective response, ultrasound should not be 
used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and 
thyroid nodules.  Ultrasound may also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.
Endoscopy and Laparoscopy:
Use of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated.  Therefore, use of these techniques for objective 
tumor response should be restricted to validation purposes in specialized centers.  
Such techniques can be useful in confirming complete pathological response 
when biopsies are obtained.
Tumor Markers:
Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper limit of normal, they must normalize for a patient to be 
considered in complete clinical response when all lesions have disappeared.
Cytology and Histology:
Cytology and histology can be used to differentiate between partial response (PR) 
and complete response (CR) in rare cases (e.g., after treatment to differentiate 
between residual benign lesions and residual malignant lesions in tumor types 
such as germ cell tumors).


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Appendix F: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Response Criteria
Evaluation of Target Lesions
Complete Response (CR): 
Disappearance of all target lesions.  
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum diameters.
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest (nadir) sum of diameters 
since the treatment started.
Progressive Disease (PD):  
At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest (nadir) sum since the treatment started, or the 
appearance of one or more new lesions.  Requires not only 20% increase, but 
absolute increase of a minimum of 5 mm over sum.
Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of tumor markers.  
All lymph nodes must be non-pathological in size (<10 mm short axis).
Stable Disease (SD):   
Persistence of one or more non-target lesions and/or persistence of tumor 
marker level above the normal limits.
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  When the patient also has measurable disease, to 
achieve “unequivocal progression” on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in the target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy.
Evaluation of Best Overall Response
As detailed above, the best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).  
In general, the patient’s best response assignment will depend on the achievement of both measurement and 
confirmation criteria.  
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is required for trials in 
which response rate is the primary endpoint, but is not required in randomized trials or trials with primary survival 
endpoints (i.e., where response is not a primary endpoint).


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
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Appendix F: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
NO
CR
CR
SD
NO
PR
CR
NE
NO
PR
PR
SD OR NE
NO
PR
SD
SD OR NE
NO
SD
PD
ANY
YES OR NO
PD
ANY
PD
YES OR NO
PD
ANY
ANY
YES
PD
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the evaluation 
of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle 
aspirate or biopsy to confirm the CR status. 
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” size (<10 mm), they 
may still have a measurement reported on scans.  This measurement should be recorded even though the nodes are 
normal in order not to overstate progression, should it be based on increase in size of the nodes.  As noted earlier, 
this means that patients with CR may not have a total sum of “zero” on the CRF.


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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015
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Appendix G: Drugs That Prolong QT Interval and/or Induce Torsades de Pointes
All QT-prolonging drugs listed below should be avoided for all patients from screening through 
permanent discontinuation of study treatment.   
Drug
QT risk(*)
Comment
Amiodarone
Known risk for TdP
Females>Males,TdP risk regarded as low
Arsenic trioxide
Known risk for TdP
Astemizole
Known risk for TdP
No Longer available in U.S.
Bepridil
Known risk for TdP
Females>Males
Chloroquine
Known risk for TdP
Chlorpromazine
Known risk for TdP
Cisapride
Known risk for TdP
Restricted availability; Females>Males.
Disopyramide
Known risk for TdP
Females>Males
Dofetilide
Known risk for TdP
Domperidone
Known risk for TdP
Not available in the U.S.
Droperidol
Known risk for TdP
Halofantrine
Known risk for TdP
Females>Males
Haloperidol
Known risk for TdP
When given intravenously or at higher-than-
recommended doses, risk of sudden death, QT 
prolongation and torsades increases.
Ibutilide
Known risk for TdP
Females>Males
Levomethadyl
Known risk for TdP
Mesoridazine
Known risk for TdP
Methadone
Known risk for TdP
Females>Males
Pentamidine
Known risk for TdP
Females>Males
Pimozide
Known risk for TdP
Females>Males
Probucol
Known risk for TdP
No longer available in U.S.
Procainamide
Known risk for TdP
Quetiapine
Possible risk for TdP
This drug is a sensitive 3A4 substrate
Quinidine
Known risk for TdP
Females>Males
Sotalol
Known risk for TdP
Females>Males
Sparfloxacin
Known risk for TdP
Tacrolimus
Possible risk for TdP
This drug is a sensitive 3A4 sibstrate with narrow TI
Terfenadine
Known risk for TdP
No longer available in U.S.
Thioridazine
Known risk for TdP
Vardenafil
Possible risk for TdP
This drug is a sensitive 3A4 substrate
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme.


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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015
Version 3.0
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Appendix H: List of QT Prolonging Drugs to be Used with Caution
Below is a list of drugs with a known risk for Torsades de Pointes (TdP).
Drug
QT risk
Comment
Alfuzosin
possible risk for TdP
Amantadine
possible risk for TdP
Amitriptyline
conditional risk for TdP
Azithromycin
possible risk for TdP
Chloral hydrate
possible risk for TdP
Citalopram
conditional risk for TdP
Clomipramine
conditional risk for TdP
Clozapine
possible risk for TdP
Desipramine
conditional risk for TdP
Diphenhydramine
conditional risk for TdP
Dolasetron
possible risk for TdP
Doxepin
conditional risk for TdP
Dronedarone
possible risk for TdP
Felbamate
possible risk for TdP
Flecainide
possible risk for TdP
Fluoxetine
conditional risk for TdP
Foscarnet
possible risk for TdP
Fosphenytoin
possible risk for TdP
Galantamine
conditional risk for TdP
Gatifloxacin
possible risk for TdP
Gemifloxacin
possible risk for TdP
Granisetron
possible risk for TdP
Imipramine
conditional risk for TdP
Indapamide
possible risk for TdP
Isradipine
possible risk for TdP
Levofloxacin
possible risk for TdP
Lithium
possible risk for TdP
Mexiletine
conditional risk for TdP
Moexipril/HCTZ
possible risk for TdP
Moxifloxacin
possible risk for TdP
Nicardipine
possible risk for TdP
Nortriptyline
conditional risk for TdP
Octreotide
possible risk for TdP
Ofloxacin
possible risk for TdP


CONFIDENTIAL
STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015
Version 3.0
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Appendix H: List of QT Prolonging Drugs to be Used with Caution (continued)
Drug
QT risk
Comment
Ondansetron
possible risk for TdP
Oxytocin
possible risk for TdP
Paliperidone
possible risk for TdP
Paroxetine
conditional risk for TdP
Perflutren lipid 
microspheres
possible risk for TdP
Protriptyline
conditional risk for TdP
Ranolazine
possible risk for TdP
Risperidone
possible risk for TdP
Roxithromycin*
possible risk for TdP
*not available in the United 
States
Sertindole
possible risk for TdP
Sertraline
conditional risk for TdP
Solifenacin
conditional risk for TdP
Tizanidine
possible risk for TdP
Trazodone
conditional risk for TdP
Trimethoprim-Sulfa
conditional risk for TdP
Trimipramine
conditional risk for TdP
Venlafaxine
possible risk for TdP
Ziprasidone
possible risk for TdP
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT


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STUDY DRUG(S): LY3023414
SCRI INNOVATIONS/SPONSOR STUDY NUMBER(S): LUN 288/I6A-MC-CBBE
AMENDMENT 2:  23 November 2015
Version 3.0
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Appendix I: Common CYP1A2 Inducers, Substrates for CYP3A4, CYP3A Inducers and 
Inhibitors, and P-gp/CYP3A Dual Inhibitors 
The following list describes medications and foods which are common inhibitors, inducers and substrates 
of CYP2C9 and CYP2C19, substrates of CYP34A, inducers of CYP2C8, inducers and inhibitors of 
CYP3A, and dual inhibitors of PgP and CYP3A.  
This list should not be considered all-inclusive.  
CYP1A2 Inducers
Moderate Inducers
50-80% decrease in AUC:

montelukast 

phenytoin
Weak Inducers
20-50% decrease in AUC:

moricizine

omeprazole 

phenobarbital
CYP3A4 Substrates with Narrow Therapeutic Range
CYP3A4 Substrates (Oral Administration)

Alfentanil 

Astemizole 

Cisapride 

Cyclosporine 

Dihydroergotamine 

Ergotamine 

Fentanyl 

Pimozide

Quinidine

Sirolimus

Tacrolimus

Terfenadine

Midazolam 

Buspirone
CYP3A/P-gp Dual Inhibitors
Strong:

Clarithromycin

Conivaptan

Diltiazem

Dronedarone

Indinavir/ritonavir

Itraconazole

Ketoconazole

Lopinavir/ritonavir

Ritonavir
Moderate:

Diltiazem

Dronedarone

Erythromycin

Verapamil


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Appendix I:
Common CYP1A2 Inducers, Substrates for CYP3A4, CYP3A Inducers and 
Inhibitors, and P-gp/CYP3A Dual Inhibitors (continued)
CYP3A Inducers
CYP3A Inhibitors
Strong:

Avasimibe

Carbamazepine

Phenytoin

Rifampin (rifampicin)

St. John’s wort (hypericum perforatum)
Strong:

Boceprevir

Clarithromycin

Conivaptan

Grapefruit juice

Indinavir

Itraconazole

Ketoconazole

Lopinavir/ritonavir

Mibefradil

Nefazodone

Nelfinavir

Posaconazole 

Ritonavir

Saquinavir

Telaprevir

Telithromycin

Voriconazole
Moderate:

Amprenavir

Aprepitant

Atazanavir

Ciprofloxacin

Cyclosporine

Darunavir/ritonavir

Diltiazem

Erythromycin

Fluconazole

Fosamprenavir

Grapefruit juice (citrus parasidi fruit juice)

Imatinib

Verapamil
Source: FDA’s Drug Development and Drug Interactions: Table of Substrates, Inhibitors and the University of Washington’s 
Drug Interaction Database.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm


Leo Document ID = 3888337a-e578-472b-a7a1-d2421fffec1c
Approver: 
Approval Date & Time: 16-Dec-2015 16:23:39 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 16-Dec-2015 17:58:15 GMT
Signature meaning: Approved
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PPD

SAP_001.pdf: 
Statistical Analysis Plan I6A-MC-CBBE (a) 
 
A Phase II Study of the Combination of LY3023414 and Necitumumab after First-Line 
Chemotherapy for Metastatic Squamous Non-small Cell Carcinoma of the Lung 
 
NCT02443337  
 
Approval Date: 28 December 2015 
 






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PPD
PPD
PPD
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CCI
CCI
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