Conditions: Non-small Cell Lung Cancer (NSCLC)
Keywords: erlotinib EGFR mutation naquotinib Non-small cell lung cancer (NSCLC) ASP8273 gefitinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 530
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations.

This study also assessed Overall survival (OS); Overall response rate (ORR) as assessed by IRR; PFS as assessed by the investigator; Disease control rate (DCR) as assessed by IRR; Duration of Response (DOR) by IRR; Safety of ASP8273; and Quality of Life (QOL) and patient-reported outcome (PRO) parameters.

Detailed description:

Arms:
arm 1: Participants received 300 mg of ASP8273 orally once daily in 28-day cycles until one of the discontinuation criteria was met (developed radiological progressive disease, required to receive local or systemic anti-cancer treatment, developed unacceptable toxicity, participant pregnancy, investigator decision, required to receive significant surgical procedure, participant protocol deviation or noncompliance, participant decline of further treatment and participant lost to follow-up). arm 2: Participants received 150 mg of erlotinib or 250 mg of gefitinib orally once daily in 28-day cycles until one of the discontinuation criteria was met (developed radiological progressive disease, required to receive local or systemic anti-cancer treatment, developed unacceptable toxicity, participant pregnancy, investigator decision, required to receive significant surgical procedure, participant protocol deviation or noncompliance, participant decline of further treatment and participant lost to follow-up).

Interventions: intervention 1: naquotinib mesilate intervention 2: Erlotinib intervention 3: Gefitinib
Intervention descriptions: intervention 1: Participants received ASP8273 300 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after taking drug) at approximately the same time every day. intervention 2: Participants received erlotinib 150 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after taking drug) at approximately the same time every day. At the beginning of the trial, prior to site initiation and shipment of study drug supplies, each investigator selected either erlotinib or gefitinib to be utilized for all participants randomized to the comparator arm at their site. intervention 3: Participants received gefitinib 250 mg was taken orally once daily with water, with or without food, at approximately the same time every day. At the beginning of the trial, prior to site initiation and shipment of study drug supplies, each investigator selected either erlotinib or gefitinib to be utilized for all participants randomized to the comparator arm at their site.

Protocol document:
Prot_000.pdf: 
An Open-label, Randomized Phase 3 Efficacy Study of 
ASP8273 vs Erlotinib or Gefitinib in First-line Treatment 
of Patients with Stage IIIB/IV Non-small Cell Lung 
Cancer Tumors with EGFR Activating Mutations
(SOLAR Study)
ISN/Protocol 8273-CL-0302
ClinicalTrials.gov Identifier: NCT02588261
Date of Protocol: Version 2.0, dated 19 Feb 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 1 of 131
Version 2.0 Incorporating Substantial Amendment 1 
An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 
vs Erlotinib or Gefitinib in First-line Treatment of Patients 
with Stage IIIB/IV Non-small Cell Lung Cancer Tumors 
with EGFR Activating Mutations
SOLAR Study
Protocol for Phase 3 Study of ASP8273
ISN/Protocol 8273-CL-0302
Version 2.0
Incorporating Substantial Amendment 1 [See Attachment 1]
19 February 2016
IND 119,902
EudraCT 2015-002894-39
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History: 
Version 1.0 Original [29Jul2015]
Investigator: Investigator information is on file at Astellas.
This confidential document is the property of the sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the sponsor.


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 2 of 131
Version 2.0 Incorporating Substantial Amendment 1 
Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························11
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················13
IV.
SYNOPSIS··························································································17
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································28
1
INTRODUCTION·················································································33
1.1
Background ····················································································33
1.2
Nonclinical and Clinical Data ·······························································34
1.2.1
Nonclinical Pharmacology ·····························································34
1.2.2
Nonclinical Pharmacokinetics ·························································34
1.2.3
Nonclinical Toxicology·································································35
1.2.4
Clinical Data ·············································································37
1.3
Summary of Key Safety Information for Study Drugs ···································37
1.3.1
ASP8273··················································································37
1.3.2
Erlotinib ··················································································38
1.3.3
Gefitinib ··················································································38
1.4
Risk-Benefit Assessment·····································································38
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································39
2.1
Study Objectives ··············································································39
2.1.1
Primary Objective ·······································································39
2.1.2
Secondary Objectives ···································································39
2.1.3
Exploratory Objectives ·································································40
2.2
Study Design and Dose Rationale···························································40
2.2.1
Study Design·············································································40
2.2.2
Dose Rationale···········································································41
2.3
Endpoints·······················································································42
2.3.1
Primary Endpoints·······································································42
2.3.2
Secondary Endpoints····································································42
2.3.3
Exploratory Endpoints ··································································42
3
STUDY POPULATION··········································································42
3.1
Selection of Study Population ·······························································42
3.2
Inclusion Criteria··············································································42


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 3 of 131
Version 2.0 Incorporating Substantial Amendment 1 
3.3
Exclusion Criteria ·············································································44
4
TREATMENT(S)··················································································46
4.1
Identification of Investigational Product(s) ················································46
4.1.1
Test Drug(s)··············································································46
4.1.2
Comparative Drug(s)····································································46
4.2
Packaging and Labeling ······································································46
4.3
Study Drug Handling ·········································································47
4.4
Blinding ························································································47
4.5
Assignment and Allocation ··································································47
5
TREATMENTS AND EVALUATION························································48
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················48
5.1.1
Dose/Dose Regimen and Administration Period ····································48
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································48
5.1.2.1
ASP8273 Dose Modification·····················································49
5.1.2.2
Erlotinib Dose Modification······················································51
5.1.2.3
Gefitinib Dose Modification ·····················································53
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································53
5.1.4
Treatment Compliance··································································55
5.2
Demographics and Baseline Characteristics ···············································55
5.2.1
Demographics············································································55
5.2.2
Medical History··········································································55
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············56
5.2.4
Performance Status······································································56
5.3
Efficacy Assessment··········································································56
5.3.1
Evaluation of Target Lesions ··························································57
5.3.1.1
Complete Response (CR)·························································57
5.3.1.2
Partial Response (PR) ·····························································57
5.3.1.3
Stable Disease (SD) ·······························································57
5.3.1.4
Progressive Disease (PD)·························································57
5.3.2
Evaluation of Nontarget Lesions ······················································57
5.3.2.1
Complete Response (CR)·························································58
5.3.2.2
NonCR/NonPD ····································································58
5.3.2.3
Progressive Disease (PD)·························································58


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 4 of 131
Version 2.0 Incorporating Substantial Amendment 1 
5.3.3
Evaluation of Time Point Response···················································58
5.3.4
Disease Control Rate (DCR)···························································58
5.3.5
Progression-free Survival (PFS)·······················································58
5.4
Safety Assessment ············································································58
5.4.1
Vital Signs················································································58
5.4.2
Adverse Events ··········································································58
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································59
5.4.3
Laboratory Assessments································································59
5.4.4
Physical Examination···································································59
5.4.5
Electrocardiogram (ECG) ······························································59
5.5
Adverse Events and Other Safety Aspects ·················································60
5.5.1
Definition of Adverse Events (AEs) ··················································60
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································60
5.5.3
Criteria for Causal Relationship to the Study Drug ·································61
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························62
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································62
5.5.6
Follow-up of Adverse Events··························································64
5.5.7
Monitoring of Common Serious Adverse Events ···································64
5.5.8
Procedure in Case of Pregnancy·······················································64
5.5.9
Emergency Procedures and Management of Overdose ·····························65
5.5.10
Supply of New Information Affecting the Conduct of the Study··················65
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid 
Life-threatening Risks to Subjects (Unique to Japan)·······························65
5.6
Test Drug Concentration ·····································································66
5.6.1
Pharmacokinetics········································································66
5.7
Other Measurements, Assessments or Methods ···········································66
5.7.1
Quality of Life and Patient Reported Outcomes·····································66
5.7.1.1
FACT-EGFRI-18 ··································································66
5.7.1.2
EORTC-QLQ-LC13·······························································66
5.7.1.3
EORTC-QLQ-C30 ································································66
5.7.1.4
EQ-5D-5L ··········································································66
5.7.2
Biomarkers ···············································································67
5.7.3
Sample for PGx Substudy ······························································67
5.8
Total Amount of Blood·······································································67
6
DISCONTINUATION············································································68


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 5 of 131
Version 2.0 Incorporating Substantial Amendment 1 
6.1
Discontinuation of Individual Subject(s)···················································68
6.2
Discontinuation of the Site···································································70
6.3
Discontinuation of the Study·································································70
7
STATISTICAL METHODOLOGY ···························································70
7.1
Sample Size····················································································70
7.2
Analysis Set····················································································70
7.2.1
Full Analysis Set (FAS) ································································71
7.2.2
Per Protocol Set (PPS) ··································································71
7.2.3
Safety Analysis Set (SAF)······························································71
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································71
7.2.5
Pharmacodynamics Analysis Set (PDAS)············································71
7.3
Demographics and Other Baseline Characteristics········································71
7.4
Analysis of Efficacy ··········································································71
7.4.1
Analysis of Primary Endpoint ·························································72
7.4.1.1
Primary Analysis···································································72
7.4.1.2
Secondary Analysis································································72
7.4.1.3
Subgroup Analysis·································································72
7.4.2
Analysis of Secondary Endpoints ·····················································72
7.4.2.1
Overall survival ····································································72
7.4.2.2
Best overall response rate (ORR)················································73
7.4.2.3
PFS by the Investigator ···························································73
7.4.2.4
Disease Control Rate (DCR) ·····················································73
7.4.2.5
Duration of Response (DOR) ····················································74
7.4.2.6
QoL and PRO Parameters ························································74
7.4.3
Analysis of Exploratory Endpoints····················································74
7.4.3.1
PFS on Next-Line Therapy (PFS#2) ············································74
7.4.3.2
Other Exploratory Analyses ······················································74
7.5
Analysis of Safety·············································································75
7.5.1
Adverse Events ··········································································75
7.5.2
Laboratory Assessments································································75
7.5.3
Vital Signs················································································75
7.5.4
Physical Examination ···································································75
7.5.5
ECGs······················································································75
7.5.6
Concomitant Medication ·······························································75


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
19 Feb 2016
Astellas
Page 6 of 131
Version 2.0 Incorporating Substantial Amendment 1 
7.5.7
ECOG Performance Status ·····························································75
7.6
Analysis of Pharmacokinetics ·······························································75
7.7
Analysis of Biomarkers·······································································76
7.8
Protocol Deviations and Other Analyses···················································76
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················76
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········77
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················77
8.1
Procedure for Clinical Study Quality Control ·············································77
8.1.1
Data Collection ··········································································77
8.1.2
Specification of Source Documents···················································78
8.1.3
Clinical Study Monitoring······························································78
8.1.4
Direct Access to Source Data/Documents············································78
8.1.5
Data Management ·······································································78
8.1.6
Protocol Deviations ·····································································79
8.1.7
End of Trial in All Participating Countries···········································79
8.2
Ethics and Protection of Subject Confidentiality··········································80
8.2.1
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ···················································80
8.2.2
Ethical Conduct of the Study···························································80
8.2.3
Informed Consent of Subjects ·························································80
8.2.3.1
Subject Information and Consent················································80
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························81
8.2.4
Subject Confidentiality ·································································81
8.3
Administrative Matters ·······································································82
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····82
8.3.2
Documents and Records Related to the Clinical Study ·····························82
8.3.3
Protocol Amendment and/or Revision················································82
8.3.4
Insurance of Subjects and Others······················································83
8.3.5
Signatory Investigator for Clinical Study Report····································83
9
QUALITY ASSURANCE········································································83
10
STUDY ORGANIZATION······································································84
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ···········84


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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10.2
Other Study Organization ····································································84
11
REFERENCES ····················································································85
12
APPENDICES ·····················································································87
12.1
List of Excluded Concomitant Medications················································87
12.2
Liver Safety Monitoring and Assessment ··················································88
12.3
Common Serious Adverse Events···························································91
12.4
Retrospective PGx Substudy·································································92
12.5
FACT-EGFRI-18··············································································94
12.6
EORTC-QLQ-LC13 ··········································································95
12.7
EORTC-QLQ-30··············································································96
12.8
EQ-5D-5L······················································································98
12.9
RECIST V1.1················································································ 100
12.10
ECOG Performance Status································································· 102
12.11
Laboratory Assessments···································································· 103
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1 ······························· 104
14
SPONSOR’S SIGNATURES·································································· 131
List of In-text Tables
Table 1
Schedule of Assessments·····································································29
Table 2
Posttreatment Discontinuation Schedule of Assessments ································32
Table 3
ASP8273 Dose Modification ································································49
Table 4
Events Requiring ASP8273 Dose Modification···········································49
Table 5
Erlotinib Dose Modification ·································································51
Table 6
Events Requiring Erlotinib Dose Modification············································52


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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19 Feb 2016
Astellas
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Version 2.0 Incorporating Substantial Amendment 1 
I.
SIGNATURES
1.  SPONSOR’S SIGNATURE
Required signatures (e.g., protocol authors, sponsor’s reviewers and contributors, etc.) are 
located in [Section 14] Sponsor’s Signatures; e-signatures (when applicable) are located at 
the end of this document.


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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2. COORDINATING INVESTIGATOR’S SIGNATURE 
An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or 
Gefitinib in First-line Treatment of Patients with Stage IIIB/IV Non-small Cell 
Lung Cancer Tumors with EGFR Activating Mutations
ISN/Protocol 8273-CL-0302
Version 2.0 / Incorporating Substantial Amendment 1
19 February 2016
I have read all pages of this clinical study protocol for which Astellas is the sponsor.  I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:


Sponsor: APGD
ISN/Protocol 8273-CL-0302
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Version 2.0 Incorporating Substantial Amendment 1 
3.  INVESTIGATOR’S SIGNATURE
An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or 
Gefitinib in First-line Treatment of Patients with Stage IIIB/IV Non-small Cell 
Lung Cancer Tumors with EGFR Activating Mutations
ISN/Protocol 8273-CL-0302
Version 2.0 / Incorporating Substantial Amendment 1
19 February 2016
I have read all pages of this clinical study protocol for which Astellas is the sponsor.  I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein.  I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations.  I will also ensure that subinvestigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:






Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
AGP
α-acid glycoprotein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANC
Absolute neutrophil count
AntiHCV
Hepatitis C antibody
APEL
Astellas Pharma Europe Limited
APGD
Astellas Pharma Global Development
APTT
Activated partial thromboplastin time
AREC
Astellas Research Ethics Committee
AST
Aspartate aminotransferase (GOT)
AUC
Area under the concentration – time curve
AUCinf
Area under the concentration – time curve from time 0 extrapolated to infinity
AUClast
Area under the concentration – time curve from time 0 up to the last quantifiable 
concentration
AUST
Astellas US Technologies
BUN
Blood urea nitrogen
CA
Competent authority
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine phosphokinase
CL/F
Apparent oral systemic clearance
CLtot
Total clearance
CNS
Central nervous system
CR
Complete response
CRF
Case report form
CRM
Continual reassessment method
CRO
Contract research organization
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
eCTD
Electronic Common Technical Document
CV
Coefficient of variation
CYP
Cytochrome P450
CYP3A4
Cytochrome P450 3A4
DCR
Disease control rate
DILI
Drug-induced liver injury
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
eGFR
Estimated glomerular filtration rate
EORTC-QLQ-
LC13
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Lung Cancer 13
EORTC-QLQ-
European Organisation for Research and Treatment of Cancer Core Quality of 


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Abbreviations
Description of abbreviations
C30
Life Questionnaire
EQ-5D-5L
EuroQol 5-Dimension 5-Level Questionnaire 
EU
European Union
FACT-EGFRI-18
Functional Assessment of Cancer Therapy – EGFRI 18 Questionnaire
FAS
Full analysis set
FFPE
Formalin Fixed Paraffin Embedded
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GWAS
Genome-Wide Association Studies
HBsAg
Hepatitis B surface antigen
Hct
Hematocrit
HDL
High density lipoprotein
Hgb
Hemoglobin
HIPAA
Health Insurance Portability And Accountability Act
HIV
Human immunodeficiency virus
HNSTD
Highest nonseverely toxic dose
HR
Hazard ratio
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICR
Imprinting control region
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IRR
Independent radiologic review
IRT
Interactive Response Technology
ISN
International Study Number
IUD
Intrauterine device
IUS
Intrauterine system
J-NDA
Japan New Drug Application
Kinact
Inactivation rate constant
KM
Kaplan-Meier
LA
Latin America
LA-CRF
Liver abnormality case report form
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LFT
Liver function tests
LSO
Last subject out
MAA
Marketing Authorization Application
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease


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ISN/Protocol 8273-CL-0302
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Abbreviations
Description of abbreviations
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NA
North America
NASH
Nonalcoholic steatohepatitis
NCI
National Cancer Institute
NDA
New Drug Application
NOAEL
No observed adverse effect level
NSCLC
Non-small-cell lung cancer
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PDAS
Pharmacodynamic analysis set
PET-CT
Positron emission tomography
PFS
Progression free survival
PFS#1
Disease progression on study drug
PFS#2
Progression free survival on next-line therapy
P-gp
Permeability-glycoprotein
PGx
Pharmacogenomic(s)
PHI
Protected health information
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PR
Partial response
PRO
Patient-reported outcome
PT
Prothrombin time
QTcF
Fridericia corrected QT interval
QoL
Quality of life
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SD
Stable disease
SOC
System organ class
SOP
Standard operating procedure
STD10
Severely toxic dose in 10%
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
TLF
Tables, listings and figures
tmax
The time after dosing when Cmax occurs
TNM
TNM Classification of Malignant Tumors
TP
Total protein
ULN
Upper limit of normal
Vss
Steady state volume of distribution
Vz/F
Apparent volume of distribution
WBC
White blood cell
WHO
World Health Organization 


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ISN/Protocol 8273-CL-0302
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Version 2.0 Incorporating Substantial Amendment 1 
Definition of Key Study Terms
Terms
Definition of terms
Baseline 
Observed values/findings which are regarded observed starting point for 
comparison.  
Enroll
To register or enter into a clinical trial.  NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.  
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study.  (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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19 Feb 2016
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Version 2.0 Incorporating Substantial Amendment 1 
IV.
SYNOPSIS
Date and Version No of Protocol Synopsis: 
19 February 2016 / Version 2.0 
Sponsor:  
Astellas Pharma Global Development Inc. (APGD)
Protocol Number:  
8273-CL-0302
Name of Study Drug: 
ASP8273
Phase of Development:  
3
Title of Study:  
An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in 
First-line Treatment of Patients with Stage IIIB/IV Non-small Cell Lung Cancer Tumors with EGFR
Activating Mutations
Planned Study Period: 
4Q2015 to 4Q2018
Study Objective(s): 
Primary

To evaluate the progression free survival (PFS), based on independent radiologic review (IRR), 
of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or 
unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal 
growth factor receptor (EGFR) activating mutations
Secondary

Overall survival (OS)

Overall response rate (ORR) as assessed by IRR

PFS as assessed by the investigator

Disease control rate (DCR) as assessed by IRR 

Duration of Response (DOR) as assessed by IRR

Safety of ASP8273

To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) parameters as measured 
by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-QLQ-C30 and EQ-5D-5L
Exploratory

To evaluate potential biomarkers that may affect treatment outcome

Evaluation of the pharmacokinetics of ASP8273

To evaluate the impact of subsequent therapy on progression free survival on next-line therapy 
(PFS#2)
Planned Total Number of Study Centers and Location(s):  
Approximately 240 centers (Globally)
Study Population:
Subjects with locally advanced, metastatic or unresectable Stage IIIB/IV adenocarcinoma NSCLC 
with EGFR activating mutations (exon 19 deletion or exon 21 L858R), with or without a T790M 
mutation, who have not previously been treated with an EGFR inhibitor (1st line).
Number of Subjects to be Enrolled/Randomized:
Approximately 600 subjects  


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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Version 2.0 Incorporating Substantial Amendment 1 
Study Design Overview:  
This multinational, open-label randomized study will evaluate ASP8273 compared to erlotinib or 
gefitinib (1st generation EGFR tyrosine kinase inhibitor [TKI]) as first line therapy in subjects with 
locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma NSCLC (newly diagnosed 
or recurrent) with EGFR activating mutations (exon 19 deletion or exon 21 L858R), with or without a 
T790M mutation, who have not previously been treated with an EGFR inhibitor (1st line).
PFS by IRR is the primary variable. Secondary variables include OS, ORR, PFS by the investigator, 
DCR, DOR, safety and QoL/PRO. Exploratory variables include biomarkers, pharmacokinetics and
PFS #2 on subsequent therapy.
Approximately 600 subjects will be randomized 1:1 to 1 of 2 treatment arms (Arm A or Arm B).  
Arm A will receive 300 mg daily of ASP8273 and Arm B will receive either 150 mg erlotinib or 
250 mg gefitinib daily, as decided by the investigator for each site at the beginning of the trial. Both 
arms will follow 28-day cycles of continuous dosing.  Subjects will be stratified according to the 
following:  ECOG PS (0, 1 or 2), EGFR mutation status (exon 19 deletion or mutations in exon 21 
[L858R]), TKI chosen (erlotinib or gefitinib) and race (Asian versus non-Asian).
Screening will take place up to 28 days prior to subject randomization on cycle 1 day 1. Subjects will 
start with cycle 1 and continue on to subsequent 28-day cycles until 1 of the discontinuation criteria 
are met. Subjects will visit the clinic for evaluations on day 1 and day 15 of treatment cycle 1 and 
then on day 1 of subsequent treatment cycles up to cycle 7. Subjects who continue past cycle 7 will 
have visits on day 1 of each odd-numbered cycle.  
Quality of life will be assessed during each treatment cycle where a visit takes place, at the follow-up 
visit, and at each of the posttreatment or long-term follow-up survival contacts for 6 months after 
treatment discontinuation (EQ-5D-5L only).
Imaging will be evaluated at baseline and every 56 days (± 7 days) throughout the study. Imaging of 
the brain is required at baseline for all subjects, and may be repeated throughout the study as 
clinically indicated.  If a brain lesion not previously irradiated is selected as a target lesion at baseline, 
the assessment should be repeated at all subsequent imaging timepoints. A blinded independent 
central reader will review all imaging scans to confirm complete response (CR), partial response 
(PR), stable disease (SD) or progressive disease (PD) per Response Evaluation Criteria in Solid 
Tumors (RECIST) V1.1. Disease progression on study drug (PFS#1) should be confirmed by the 
blinded independent central reader before subjects are discontinued from treatment.  
Following discontinuation from study drug, subjects will have a follow-up visit 30 days (+ 7 days) 
after their last dose of drug for safety assessments. If a subject discontinues study drug prior to 
radiographic disease progression (i.e., PFS#1), the subject should enter the posttreatment follow-up 
period and continue to undergo imaging assessments every 56 days (±7 days) until PFS#1 is 
documented or the subject starts another anticancer treatment, whichever occurs earlier. 
Following PFS#1, subjects will enter the long-term follow-up period and be followed every 3 months 
from the date of the follow-up visit for survival status and progression status on subsequent therapy
(i.e., PFS #2). Subjects will be followed until PFS#2 is documented or the subject starts another 
anticancer treatment, whichever occurs earlier. All subsequent anticancer therapy including date and 
site of progression for PFS#2 will be recorded on the case report form. Following PFS#2, subjects 
will enter the survival follow-up period and be followed every 3 months for survival status.
Samples for pharmacokinetics, biomarkers and pharmacogenomics (PGx) as well as formalin fixed 
paraffin embedded (FFPE) specimens for central analysis will be collected.  Eligibility may be 
determined by a previously documented EGFR mutation result. However, there should be sufficient 
tissue from the specimen used to generate the EGFR test result to send to the central lab for 
confirmatory testing.  If a subject does not have a previously documented EGFR mutation test result, 
then a fresh specimen must be obtained and sent to the central lab for eligibility testing. An optional 


Sponsor: APGD
ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
- CONFIDENTIAL -
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Version 2.0 Incorporating Substantial Amendment 1 
post-progression tumor tissue sample for exploratory analysis of biomarkers (e.g., EGFR mutation 
[T790M, C797S], c-Met mutation/amplification and AXL over expression) which are potentially 
related to EGFR-TKI drug response or resistance may be collected following locally or centrally 
confirmed disease progression for subjects who sign a separate informed consent form (ICF).
An independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and the 
planned interim futility analysis which will occur after at least 210 PFS#1 events have been observed.
The primary analysis will occur when at least 420 PFS#1 events are observed which is expected to 
occur approximately 36 months after randomization of the first subject. Primary endpoint, secondary 
endpoints and other endpoints will be analyzed at the time of primary analysis.
Inclusion/Exclusion Criteria:  
Inclusion Criteria
Subject must meet all of the following inclusion criteria to be eligible for participation in this study at 
enrollment:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., HIPAA Authorization for 
U.S. sites) must be obtained from the subject or legally authorized representative prior to any 
study-related procedures.
2.
Subject is ≥ 18 years of age and legally an adult according to local regulation at the time of 
signing informed consent.
3.
Subject agrees not to participate in another interventional study while on treatment.
4.
Female subject must either:
Be of nonchildbearing potential:
o
postmenopausal (defined as at least 1 year without any menses) prior to Screening, or 
o
documented surgically sterile
Or, if of childbearing potential:
o
Agree not to try to become pregnant during the study and for 28 days after the final 
study drug administration
o
And have a negative serum pregnancy test at Screening 
o
And, if heterosexually active, agree to consistently use 2 forms of birth control* (at 
least 1 of which must be a highly effective method* and one must be a barrier method) 
starting at Screening and throughout the study period and for 28 days after the final 
study drug administration
5.
Female subject must not be breastfeeding at Screening or during the study period, and for 28 days 
after the final study drug administration.
6.
Female subject must not donate ova starting at Screening and throughout the study period, and for 
28 days after the final study drug administration.
7.
Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control* (1 of which must be a 
barrier method) starting at Screening and continue throughout the study period and for 90 days 
after the final study drug administration.
*Highly effective forms of birth control include:
Consistent and correct usage of established oral, injected or implanted hormonal methods 
of contraception
Established intrauterine device (IUD) or intrauterine system (IUS)
*Acceptable forms of birth control include:
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository (not applicable in Japan and 
Thailand: with spermicidal foam/gel/film/cream/suppository)


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ISN/Protocol 8273-CL-0302
EudraCT number 2015-002894-39
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Version 2.0 Incorporating Substantial Amendment 1 
●Calendar-based contraceptive methods (Knaus-Ogino or rhythm method [Japan and 
Thailand only])
8.
Male subject must not donate sperm starting at Screening and throughout the study period and for 
90 days after the final study drug administration.
9.
Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
10. Subject has histologically confirmed locally advanced, metastatic or unresectable Stage IIIB/IV 
adenocarcinoma NSCLC (newly diagnosed or recurrent).  Subjects with mixed histology are 
eligible if adenocarcinoma is the predominant histology.
11. Subject has predicted life expectancy 12 weeks in the opinion of the investigator.
12. Subject must meet all of the following criteria on the laboratory tests that will be analyzed
centrally within 7 days prior to the first dose of study drug.  In case of multiple laboratory data 
within this period, the most recent data should be used.

Neutrophil count > 1,000/mm3

Platelet count 7.5 104 /mm3

Hemoglobin > 8.0 g/dL

Serum creatinine 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration 
rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method

Total bilirubin 1.5 ULN (except for subjects with documented Gilbert’s syndrome)

AST and ALT 3.0 ULN or ≤ 5 ULN if subject has documented liver metastases

Serum sodium level is ≥130 mmol/L
13. Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without 
T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen
(archival or fresh biopsy).  Subjects harboring both exon 19 deletion and exon 21 L858R 
mutations are not eligible.  A tissue sample from the same block used to determine eligibility by 
local testing should be available to send to the central lab for confirmatory testing.  Subjects 
randomized based on local results indicating presence of EGFR mutation may remain on study if 
central results are discordant.
14. Subject must have at least 1 measureable lesion based on RECIST V1.1. Previously irradiated 
lesions will not be considered as measurable lesions.
Exclusion Criteria
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible for 
enrollment:
1.
Subject has received intervening anticancer treatment or previous treatment with chemotherapy 
for metastatic disease other than palliative local radiation to painful bone metastases completed at 
least 1 week prior to the first dose of study drug.  The administration of neoadjuvant or adjuvant 
chemotherapy is allowed as long as it has finalized ≥ 6 months before the first dose of study drug. 
2.
Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, 
dacomitinib, ASP8273, etc).
3.
Subject has received investigational therapy within 28 days or 5 half-lives prior to the first dose of 
study drug.
4.
Subject has received radiotherapy within 1 week prior to the first dose of study drug. If the 
subject received radiotherapy > 1 week prior to study treatment, the irradiated lesion cannot be 
the only lesion used for evaluating response.


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5.
Subject has symptomatic central nervous system (CNS) metastasis.  Subject with previously 
treated brain or CNS metastases are eligible provided that the subject has recovered from any 
acute effects of radiotherapy, does not have brain metastasis related symptoms, is not requiring 
systemic steroids for at least 2 weeks prior to study drug administration, and any whole brain 
radiation therapy was completed at least 4 weeks prior to study drug administration or any 
stereotactic radiosurgery (SRS) was completed at least 2 weeks prior to study drug administration. 
Steroid inhaler use or ointment treatment for other concomitant medical disease is permitted.
6.
Subject has received blood transfusions or hematopoietic factor therapy within 14 days prior to 
the first dose of study drug.
7.
Subject has had a major surgical procedure (other than a biopsy) within 14 days prior to the first 
dose of study drug, or one is planned during the course of the study. 
8.
Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection.
9.
Subject has known history of serious hypersensitivity reaction to a known ingredient of ASP8273, 
erlotinib or gefitinib.
10. Subject has evidence of an active infection requiring systemic therapy within 14 days prior to the 
planned first dose of study drug.
11. Subject has severe or uncontrolled systemic diseases including uncontrolled hypertension (blood 
pressure > 150/100 mmHg) or active bleeding diatheses.
12. Subject has history of drug-induced interstitial lung disease (ILD) or any evidence of active ILD.
13. Subject has ongoing cardiac arrhythmia that is Grade ≥2 or uncontrolled atrial fibrillation of any 
grade. 
14. Subject currently has Class 3 or 4 New York Heart Association congestive heart failure.
15. Subject has history of severe/unstable angina, myocardial infarction or cerebrovascular accident 
within 6 months prior to the planned first dose of study drug.
16. Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months prior to 
the planned first dose of study drug.
17. Subject has concurrent corneal disorder or any ophthalmologic condition which, in the 
investigator’s opinion, makes the subject unsuitable for study participation (i.e., advanced 
cataracts, glaucoma).
18. Subject has difficulty taking oral medication or any digestive tract dysfunction or inflammatory 
bowel disease that would interfere with the intestinal absorption of drug.
19. Subject has another past or active malignancy which requires treatment.  Prior carcinoma in situ 
or non-melanoma skin cancer after curative resection are permitted.
20. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation. 
21. Subject has received potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug or 
proton pump inhibitors such as omeprazole within 14 days prior to first dose of study drug.
Investigational Product(s):
ASP8273 100 mg capsule strength
Dose(s):  
The dose is 300 mg once daily
Mode of Administration:
ASP8273 will be orally administered once daily, at approximately the same time every day on an 
empty stomach defined as no food for at least 2 hours before and 1 hour after dosing. Concomitant 
medications should not be administered within 2 hours before or after dosing with ASP8273.


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Comparative Drug(s):
Erlotinib/Gefitinib 
Dose(s):
Erlotinib 150 mg once daily or gefitinib 250 mg once daily as decided by the investigator for each site
at the beginning of the trial. 
Mode of Administration:
Erlotinib will be taken orally, at approximately the same time every day on an empty stomach defined 
as no food for at least 2 hours before and 1 hour after dosing. 
Gefitinib will be taken orally, with or without food, at approximately the same time every day.
Concomitant medications should not be administered within 2 hours before or after dosing with 
erlotinib or gefitinib.
Dose Modifications:
Dosing for ASP8273, erlotinib or gefitinib may be interrupted or reduced (ASP8273 and erlotinib 
only) for any event if the investigator deems it necessary to ensure subject safety.  Subjects requiring 
a treatment interruption should be re-evaluated not longer than 7 days from initial interruption and 
restarted on study drug as soon as clinically stable.  The subject may be discontinued from treatment 
if there is an interruption of treatment for > 14 consecutive days despite optimal treatment of side 
effects. A discussion with the Medical Monitor should occur to confirm if the subject should continue 
on study treatment.
In the event of acute onset or worsening of pulmonary symptoms likely suggestive of ILD (dyspnea, 
cough, fever), study drug should be interrupted and a prompt investigation of these symptoms should 
occur and appropriate treatment initiated.  If ILD is confirmed, study drug should be discontinued, 
and the subject should be treated appropriately per local standard of care.
Study drug should be interrupted if the subject experiences eye toxicity such as acute and severe eye 
pain or keratitis.  Subjects with suspected keratitis should have study drug withheld until recovery and 
discontinued for persistent severe keratitis.  Subjects with ocular toxicities should be evaluated by an 
ophthalmologist.
If the subject experiences severe hepatic impairment, study drug should be discontinued and the 
subject should be treated appropriately per local standard of care.
The table below summarizes ASP8273 dose modifications:
Dose level
ASP8273 dose (mg qd)
Starting dose
300
-1
200
-2
100
Subjects requiring a dose reduction may be re-escalated one dose level (i.e., subjects reduced to 
100 mg may only be re-escalated to 200 mg).  If the event leading to the reduction recurs, the subject 
should be reduced the lower dose level and not re-escalated again.  If a grade 3 or 4 study drug-related 
toxicity persists or recurs after 2 dose reductions, the subject should be permanently discontinued 
from ASP8273 treatment. Additionally, if after resolution of a Grade 4 event requiring dose 
interruption and/or dose reduction, the event reoccurs at a G3 or higher the subject should be 
permanently discontinued from ASP8273.
Please refer to Section 5.1.2 of the protocol for detailed dose modification criteria.
The table below summarizes Erlotinib dose modifications:


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Dose level
Erlotinib (mg qd)
Starting dose
150
-1
100
-2
50
Dose modifications for erlotinib are suggested for toxicities of ILD, skin rash, and diarrhea, however,
the locally approved label for erlotinib dose modification for toxicities should be followed.  Subjects 
requiring dose reduction of erlotinib may have the dose re-escalated if they have been on a stable dose 
for ≥ 3 weeks without further toxicities requiring dose modification and it is considered by the 
investigator to be in the best interest of the subject. If any toxicity requiring dose interruption of 
erlotinib recurs despite the initial dose reduction to level -1 (100 mg qd), erlotinib may be reduced 
again to level -2 (50 mg qd). If 2 levels of erlotinib dose reduction are required, subsequent 
reescalation may only be to dose level -1.
Please refer to section 5.1.2 of the protocol for detailed dose modification criteria.
Recommended therapy interruption for gefitinib is provided, however, the locally approved label for 
gefitinib dose interruption should be followed. There will be no dose reductions for subjects receiving 
gefitinib, as it is only available as single strength tablet.
Please refer to section 5.1.2 of the protocol for detailed dose modification criteria.
Discontinuation Criteria 
A discontinuation is a subject who enrolled in the study and for whom study treatment is permanently 
discontinued for any reason.  The subject is free to withdraw from the study treatment and/or study 
for any reason and at any time without giving reason for doing so and without penalty or prejudice.  
The investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
The subject will be discontinued from the treatment period if any of the following occur:

Subject develops radiological progressive disease (i.e., PFS#1) per RECIST v1.1 based on central 
confirmation of investigator assessment
o
If there is radiographic evidence of PD by investigator, however the investigator believes 
the subject is continuing to derive clinical benefit (asymptomatic and/or without worsening 
of performance status or overall health) from study drug, and an increase in tumor burden is 
not likely to affect vital organ function, the subject may remain on study drug until the next 
scheduled radiographic assessment which should occur after 56 days (± 7 days). 
o
If the next radiographic assessment indicates PD per RECIST 1.1 which is confirmed by the 
central reviewer, then the subject must be discontinued from study drug. 
o
In the rare event where PD suspected on initial assessment is not confirmed on subsequent 
scan by the investigator or central reviewer, the subject may continue in the study. 
o
The investigator should make every effort to immediately submit radiographic assessments 
for central review when PD is either suspected or confirmed or uncertainty exists.
o
In case of PD determination by the investigator, however not confirmed by the central 
reviewer, and subject is progressing clinically and requires new anti-cancer treatment 
immediately, the subject should be discontinued.

Subject is required to receive local or systemic anti-cancer treatment based on investigator’s 
clinical opinion.

Subject develops unacceptable toxicity

Female subject becomes pregnant

Investigator decides it is in the subject’s best interest to discontinue including clinical progression

Requirement for significant surgical procedure; however, if surgical procedure is for the resection 
of the primary or metastatic lesion, the subject may be eligible to continue on study treatment 
after discussion with the Medical Monitor


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
Significant deviation from the protocol or eligibility criteria

Subject declines further treatment

Subject is noncompliant with the protocol based on the investigator or Medical Monitor 
assessment

Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject

Death
Subjects who discontinue study drug and enter the posttreatment follow-up period prior to reaching 
PFS#1 will be discontinued from the posttreatment follow-up period if any of the following occur:

Subject develops radiological progressive disease (i.e., PFS#1) based on investigator assessment

Subject initiates a new systemic anticancer treatment

Subject misses 2 consecutive scheduled tumor assessments
The subject will be discontinued from the long-term follow-up period (for PFS#2) if any of the
following occur:

Subject initiates a new systemic anticancer treatment (3rd line)

Subject exhibits evidence of PD from 2nd line therapy based on investigator assessment

Subject declines further study participation (i.e., withdraws consent)

Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject

Subject misses 2 consecutive scheduled tumor assessments

Death

Sponsor ends long-term follow-up collection period
The subject will be discontinued from the survival follow-up period if any of the following occur:

Subject declines further study participation (i.e., withdraws consent)

Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject

Death

Sponsor ends survival follow-up period
Concomitant Medication Restrictions or Requirements:
Arm A (ASP8273)
The following medications/food are likely to influence evaluation of the safety, pharmacokinetics, or 
efficacy of ASP8273, and will be strictly prohibited:

Chemotherapy, radiotherapy, immunotherapy, or other medications intended for antitumor 
activity

Investigational products or therapy other than ASP8273

Potent inhibitors (e.g., ketoconazole, grapefruit or grapefruit juice) or inducers (e.g., rifampin, 
phenytoin or St. John’s wort) of CYP3A4 

CYP3A4 and/or P-gp substrates with a narrow therapeutic index
The use of the following medications should be avoided or used with caution and close monitoring:

Moderate/weak inhibitors or inducers of CYP3A4 

Inhibitors or inducers of P-gp

CYP3A4 and/or P-gp substrates
Arm B (Erlotinib/Gefitinib)
The following medications/food are likely to influence evaluation of the safety, pharmacokinetics, or 
efficacy of erlotinib/gefitinib, and will be strictly prohibited:


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
Chemotherapy, radiotherapy, immunotherapy, or other medications intended for antitumor 
activity other than erlotinib/gefitinib

Investigational products or therapy

Potent inhibitors (e.g., ketoconazole, grapefruit or grapefruit juice) or inducers (e.g., rifampin, 
phenytoin or St. John’s wort) of CYP3A4 

Proton pump inhibitors or drugs that cause significant elevation in gastric pH
The use of the following medications should be avoided or used with caution and close monitoring
while the subject is receiving erlotinib/gefitinib:

Moderate/weak inhibitors or inducers of CYP3A4 

Inhibitors or inducers of P-gp

Warfarin

For subjects who are randomized to erlotinib: 
o
Potent inhibitors of CYP1A2

For subjects who are randomized to gefitinib:
o
Potent inhibitors of CYP2D6
o
CYP2D6 substrates with narrow therapeutic index
Duration of Treatment:  
Subjects will be allowed to receive ASP8273 or erlotinib/gefitinib until discontinuation criteria are 
met.  
Endpoints for Evaluation:  
Primary 

PFS as assessed by IRR  
Secondary

OS

Best overall response rate (CR + PR) by IRR

PFS by the investigator

DCR (CR+PR+SD) by IRR

DOR by IRR

Safety variables (e.g., adverse events [AEs], laboratory tests, vital sign measurements, 
electrocardiograms [ECGs])

QoL and PRO parameters as measured by FACT-EGFRI-18, EORTC-QLQ-LC13, 
EORTC-QLQ-C30 and EQ-5D-5L
Exploratory

Plasma T790M and other biomarkers related to EGFR TKI sensitivity and/or resistance

Plasma pharmacokinetics of ASP8273

PFS#2 on subsequent therapy
Biomarkers:
Tumor tissue sample (FFPE) will be obtained and sent for central confirmatory testing to evaluate for 
EGFR activating mutation. The sample sent for confirmatory testing should be from the same 
specimen as used for local testing for eligibility. A plasma sample will be collected to evaluate EGFR 
mutations. Plasma and whole blood samples will be collected for exploratory analysis of biomarkers
(e.g. EGFR mutation [T790M, C797S], c-Met mutation/amplification, AXL over expression) which 
are potentially related to EGFR-TKI drug response or resistance. An optional post-progression tumor 
tissue sample for exploratory analysis of biomarkers  (e.g., EGFR mutation [T790M, C797S], c-Met 
mutation/amplification, and AXL over expression) which are potentially related to EGFR-TKI drug 






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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart


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Table 1
Schedule of Assessments
VISIT
Screening
Cycle 1
Cycle 2
Cycle 3-6
≥ Cycle 7
(odd cycles)
End of 
Treatment
Base Date
Day 1
Day 15
Day 1
Day 1
Day 1
Date of Last 
Dose
Visit Window
Day -28 to 0
±1 day
±3 days
±7 days
±7 days
+7 days
Informed Consent
X
Medical and Disease History
X
Confirmation of Eligibility
X
X
Randomization1
X
Study Drug Administration2
X
X
X
X
X
Physical Examination 3
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Biochemistry4
X
X
X
X
X
X
X
Hematology5
X
X
X
X
X
X
X
Coagulation Parameters6
X
X
X
X
X
Urinalysis7
X
X
X
X
X
X
Serum Pregnancy Test8
X
X
X
X
X
X
12-lead ECG9
X
X
X
X
X
X
X
Image Assessment10
X
X
X
Tumor Sample – EGFR11
X
Post-progression Tumor Sample (optional)12
X
Plasma Sample – EGFR 
X
X
Pharmacokinetics – Blood13
X
X
X
X
X
Plasma Sample –Biomarkers14
X
X
X
X
Whole Blood Sample – Biomarkers
X
Whole Blood Sample for PGx (optional)
X
Table continued on next page


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VISIT
Screening
Cycle 1
Cycle 2
Cycle 3-6
≥ Cycle 7
(odd cycles)
End of 
Treatment
Base Date
Day 1
Day 15
Day 1
Day 1
Day 1
Date of Last 
Dose
Concomitant Medication
X
X
X
X
X
X
X
Adverse Event
X
X
X
X
X
X
X
Quality of Life (QoL)15
X
X
X
X
X
X
Survival Assessment
X
X
X
X
X
X
X
1
May be performed prior to C1D1 with prior sponsor approval
2
Daily dosing, 28 days per cycle
3
Physical examination and other evaluations include height (at screening only) weight, ECOG PS, and vital signs (pulse and blood pressure). Vital signs should be taken predose on 
dosing days.  The physical exam only needs to be repeated on cycle 1 day 1 if clinically significant changes from Screening (in the opinion of the investigator) are observed.
4
Biochemistry: See [Appendix 12.11  for list of laboratory assessments. All biochemistry laboratory tests should be conducted after the subject has been fasting for at least 6 hours in 
order to ensure accurate interpretation of glucose values. Fasting status should be recorded in source documents.  Biochemistry tests will be sent to a central laboratory for analysis.  
Additional assessments may be done centrally or locally to monitor adverse events or as required by dose modification requirements.
5
Hematology: see [Appendix 12.11] for list of laboratory assessments. Hematology tests will be sent to a central laboratory for analysis,
6
Coagulation: see [Appendix 12.11  for list of laboratory assessments. Coagulation tests will be taken on day 1 of cycles 1-3 and every odd cycle thereafter (cycles 5, 7, 9 etc.).
Coagulation tests will be sent to a central laboratory for analysis.
7
Urinalysis: see [Appendix 12.11] for list of urinalysis assessments. Urinalysis tests will be sent to a central laboratory for analysis.
8
For female subjects of child bearing potential only. Serum pregnancy tests every cycle where a visit takes place will be done throughout the study.
9
ECG time points are: Screening; cycle 1 day 1 predose; cycle 1 day 15 predose; and day 1 predose of cycle 2 and each subsequent cycle where a visit takes place. When collected 
on the same day, ECG should be collected prior to pharmacokinetic samples.
10 Image assessments will be done every 56 days (± 7 days), scheduled in a way to allow results to be available for the odd cycle day 1 visit (i.e., prior to cycles 3, 5, 7, 9, etc.).  
Imaging of the brain is required at baseline for all subjects, and may be repeated throughout the study as clinically indicated.  If a brain lesion is selected as a target lesion at 
baseline, the assessment should be repeated at all subsequent imaging timepoints.  CT scan with contrast (chest and abdomen) is the preferred modality for tumor assessment. MRI 
is acceptable if local standard practice or if CT scans are contraindicated in a subject (e.g., subject is allergic to contrast media). All other RECIST-approved scanning methods such 
as X-ray are optional. PET-CT scans must use contrast. To ensure comparability, the screening and subsequent assessment of response should be performed using identical 
techniques. The same method should be employed and assessed by the same individual on each occasion if possible. Imaging assessments, including brain, should utilize the same 
methods throughout the study. Confirmation scans for CR or PR should be done at the next scheduled assessment. A chest x-ray or other appropriate imaging of the lungs should be 
performed in addition to specified imaging time points if a subject develops symptoms suggestive of ILD.
Footnotes continued on next page


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11 Eligibility may be determined by a previously documented EGFR mutation test result. However, there should be sufficient tumor tissue from the specimen used to generate the 
EGFR test result to send to the central lab for confirmatory testing. If a subject does not have a previously documented EGFR mutation test result, then a fresh specimen must be 
obtained and sent to the central lab for eligibility testing. If slides are submitted, the slides should be freshly cut from the FFPE block within 18 days of sending to the central lab. A 
plasma sample for EGFR mutation detection will also be collected and submitted to the central laboratory.  
12 For subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis should be collected following local or central confirmation of 
disease progression and prior to commencement of subsequent anticancer therapy.  
13
Pharmacokinetic samples of ASP8273 will be taken for subjects randomized to Arm A (ASP8273) at predose on cycle 1 day 15 and predose on day 1 of cycles 2, 3, 5, 9 and 13 and 
at the End of Treatment visit. The date and time of each blood sample collection will be recorded to the nearest minute.  In addition, the date and time of the ASP8273 doses taken 
on the pharmacokinetic days and the last 2 ASP8273 doses taken prior to each pharmacokinetic day will be recorded to the nearest minute.  In the event ASP8273 treatment has 
been withheld for ≥3 days prior to the timepoint, the PK sample will not be collected.
14 Plasma samples for biomarkers will be collected at predose on day 1 of each odd cycle (cycles 1, 3, 5, 7, 9 etc.) and at the End of Treatment visit. Whole blood sample for 
biomarkers will be collected once at baseline.
15 QoL questionnaires are to be administered on visit days before any other scheduled assessments are conducted and before the disease status is discussed with the subject.


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Table 2
Posttreatment Discontinuation Schedule of Assessments
VISIT
Follow-up Visit
Posttreatment Follow-up
Period
Long-term Follow-up
Period
Survival Follow-up
Period
Base Date
Date of last
Dose +30 days
Every 56 days
Every 3 months
Every 3 months
Visit Window
+7 days
±7 days
±7 days
±7 days
ECOG PS
X
Vital Signs
X
Image Assessment
X1
Subsequent therapy assessment2
X
X
X
QoL
X
QoL – EQ-5D-5L only3
X
X
Survival Assessment
X
X
X
X4
Adverse Event
X
X
1 
If a subject discontinues study drug prior to radiographic disease progression (i.e., PFS#1), the subject should continue to undergo imaging assessment (including brain imaging 
when indicated and collection of tumor measurements) every 56 days (±7 days) in the posttreatment follow-up period until PFS#1 is documented per the investigator, the subject 
misses 2 or more consecutive scheduled tumor assessments, or the subject starts another cancer treatment, whichever occurs earlier.  
2 
After PFS#1, subjects will be followed in the long-term follow-up period per institutional guidelines, but not less frequently than every 3 months to confirm survival status and 
collect subsequent anticancer treatment details and progression status until PFS#2 is documented or the subject starts another cancer treatment, whichever occurs earlier.  Phone 
contact with subject is sufficient for follow-up. Additional follow-up contacts may be required per sponsor request for analysis purposes.  
3 
Quality of life (EQ-5D-5L only) will be assessed at each of the posttreatment or long-term follow-up survival contacts for 6 months after treatment discontinuation. QoL may be 
assessed by telephone module if follow-up contact is done by phone.
4 
Subjects will be followed via phone call in the survival follow-up period approximately every 3 months to collect survival status until subject death or study closure. Additional 
follow-up contacts may be required per sponsor request for analysis purposes.


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1
INTRODUCTION
1.1
Background
Lung cancer is a leading cause of cancer death worldwide.  Lung cancer accounts for over 
1 million mortalities annually and NSCLC accounts for almost 85% of all cases [Esposito et 
al, 2010; Herbst et al, 2008; Ferlay et al, 2007].  Epidermal growth factor receptor (EGFR) 
mutations are found in approximately 10% and 30% of NSCLC patients in North American/ 
European and East Asian countries, respectively [Bell et al, 2005; Shigematsu et al, 2005].  
EGFR activating mutations result in increased malignant cell survival, proliferation, invasion, 
metastatic spread and tumor angiogenesis in NSCLC [Herbst et al, 2008; Mendelsohn & 
Baselga, 2000; Wells A, 1999].  The 2 most common EGFR mutations are short in frame 
deletions of exon 19, and a point mutation (CTG to CGG) in exon 21 at nucleotide 2573 
resulting in the substitution of leucine for arginine in codon 858 (L858R) [Herbst et al, 2008; 
Ladanyi & Pao, 2008].  These mutations account for approximately 90% of EGFR mutations 
in NSCLC [Sharma et al, 2007].
ASP8273 mesilate is a novel, small molecule irreversible tyrosine kinase inhibitor (TKI) that 
inhibits the kinase activity of EGFR containing the exon 19 deletion (del ex19) or the exon 
21 (L858R) substitution activating mutation as well as the T790M resistance mutation with 
higher potency than wild-type EGFR.
Reversible EGFR TKIs, gefitinib and erlotinib, inhibit the growth of NSCLC cell lines 
expressing EGFR activating mutations as well as wild-type EGFR.  These TKIs have shown 
antitumor efficacy and prolonged progression free survival (PFS) in NSCLC patients with 
EGFR activating mutations [Mitsudomi et al, 2012; Rosell et al, 2012; Zhou et al, 2012; 
Zhou et al, 2011; Maemondo et al, 2010; Mitsudomi et al, 2010; Mok et al, 2009].  The 
clinical efficacy of gefitinib and erlotinib is limited by the development of acquired drug 
resistance, which is most commonly caused by a T790M resistance mutation in EGFR.  This 
mutation has been detected in approximately 50% to 60% of clinically resistant patients; 
therefore, along with activating mutations, the T790M mutation is an important factor in 
treating NSCLC [Ohashi et al, 2013; Kobayashi et al, 2005; Pao et al, 2005].
In this study, ASP8273 will be studied first line in subjects who have EGFR activating 
mutations and have not been exposed to prior TKI therapy. 
Given that in addition to having a high potency to target T790M resistance mutations, 
ASP8273 mesilate also inhibits several other kinases (BLK, BMX, BTK, FLT3, HER4, ITK, 
JAK3, TEC, TNK1 and TXK).  Therefore, it is thought that treating first line subjects who 
have EGFR activating mutations with ASP8273 will delay the time to acquiring T790M 
resistance, resulting in a longer duration of PFS than gefitinib and erlotinib in a first line 
setting. 
This is supported by the fact that ASP8273 mesilate has been shown to inhibit growth of 
several human NSCLC cell lines harboring EGFR del ex19 or T790M/L858R mutation with 
higher potency than those with wild-type EGFR.  ASP8273 mesilate has induced tumor 
regression in in vivo tumor models xenografted with NSCLC cell lines harboring EGFR del 


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ex19 or T790M/L858R mutation. Results from nonclinical studies support the investigation 
of ASP8273 mesilate in patients with NSCLC, whose tumors harbor EGFR mutations.
1.2
Nonclinical and Clinical Data
1.2.1
Nonclinical Pharmacology
ASP8273 mesilate has been assessed in primary pharmacodynamics studies, as well as in 
safety pharmacology studies.  Tabulated overviews of nonclinical pharmacology studies can 
be found in the ASP8273 Investigator’s Brochure, Version 4 [30 July 2015].
ASP8273 mesilate inhibited the kinase activity of EGFR containing activating mutations, the 
del ex19 and the exon 21 (L858R) substitution mutation, and also inhibited the kinase 
activity of EGFR containing both the activating mutation and the T790M resistance mutation 
(i.e., del ex19/T790M and T790M/L858R).  In EGFR mutants (T790M/L858R), ASP8273 
mesilate covalently bound to the kinase.
ASP8273 mesilate inhibited growth of HCC827, PC-9 and NCI-H1650 cells, human NSCLC
cell lines harboring EGFR del ex19. ASP8273 mesilate also inhibited growth of NCI-H1975
cells, a human NSCLC cell line harboring EGFR mutation T790M/L858R. Antiproliferative
activity of ASP8273 mesilate in NCI-H292 and NCI-H1666 cells and human NSCLC cell 
lines harboring wild-type EGFR, was less potent than in cells harboring EGFR mutations.  
ASP8273 mesilate inhibited EGFR phosphorylation in NCI-H1975 cells and maintained
inhibition for 24 h after washout.
ASP8273 mesilate inhibited tumor growth and induced tumor regression in vivo in mice
subcutaneously xenografted with HCC827 or NCI-H1975 cells after 14-day repeat oral
administration. ASP8273 mesilate did not affect body weight at any of the doses tested.
1.2.2
Nonclinical Pharmacokinetics
After a single intravenous administration of ASP8273 mesilate at dose levels of 3 mg/kg to 
rats and 0.3 mg/kg to dogs, plasma concentrations of unchanged ASP8273 decreased with a 
t1/2 of 3.30 and 9.12 h, respectively. The total body clearance (CLtot) and the volume of 
distribution (Vss) were 1569.4 mL/h per kg and 4906.9 mL/kg in rats, and 1936.2 mL/h per 
kg and 18946.8 mL/kg in dogs, respectively. After a single oral administration of ASP8273 
mesilate at 3, 10 and 30 mg/kg to rats and 0.3, 1 and 3 mg/kg to dogs, the Cmax and the 
AUCinf increased more than dose-proportionally. The t1/2 ranged from 2.99 to 4.73 h in rats 
and 9.23 to 9.93 h in dogs.  Absolute oral bioavailability (F) was 41.0% in rats and 40.9% in 
dogs.
After oral administration of a single dose of [14C]ASP8273 mesilate at 10 mg/kg to rats,
radioactivity was moderately absorbed and distributed to the tissues. Radioactivity decreased 
time-dependently in all tissues. Some tissues such as the testes, blood, Harderian glands and
thyroid showed relatively slow elimination, with 60.4%, 49.0%, 28.0% and 20.4% of their
maximum radioactivity 72 h postadministration, respectively.


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The in vitro plasma protein binding ratios of [14C] ASP8273 at concentrations of 0.5, 5 and 
50 μg/mL ranged from 89.19% to 91.56% in ICR mice, 87.34% to 93.85% in 
H1975-xenografted nude mice, 92.07% to 95.37% in rats, 81.10% to 82.97% in rabbits, 
76.22% to 81.39% in dogs, 89.13% to 96.94% in monkeys, and 90.89% to 95.91% in 
humans. Human serum albumin and α1-acid glycoprotein (AGP) were found to be the 
primary binding proteins in human plasma.
ASP8273 metabolism by cytochrome P450 (CYP) isozymes was examined using 
16 individual human liver microsome samples. Results suggested that CYP3A4/5 is the main 
CYP isozyme involved in the metabolism of ASP8273. When [14C]ASP8273 mesilate was 
orally administered to rats at 10 mg/kg, the main component in plasma was the unchanged 
drug.  Species differences in the in vitro metabolic profiles of ASP8273 were investigated 
with [14C]ASP8273 using pooled liver microsomes and cryopreserved hepatocytes from 
mice, rats, rabbits, dogs, monkeys and humans. All major metabolite peaks detected in 
human liver microsomes and cryopreserved hepatocytes were also found in at least 1 other 
species. No clear sex differences in humans were observed in the metabolic profiles of 
ASP8273.  Structural analysis of in vitro metabolites in humans demonstrated that ASP8273 
was mainly metabolized by N-demethylation followed by the piperazine cleavage, oxidation 
and glutathione conjugation.
After oral administration of a single dose of [14C]ASP8273 mesilate at 10 mg/kg to rats, the
excretion of radioactivity in urine and feces up to 168 h after dosing was 4.2% and 88.6% of
the dose, respectively. The excretion of radioactivity in urine and bile up to 48 h after dosing
was 4.0% and 32.4% of the dose, respectively. These results suggest that orally administered
ASP8273 mesilate is mainly excreted in feces, with some excretion via the bile. When
radioactivity excreted into the bile was injected into the duodenum of other rats, the
reabsorption ratio was 0.7%.
ASP8273 showed slight direct inhibition of CYP1A2 and 2C8 (IC50 > 300 μmol/L), direct 
inhibition of CYP2B6, 2C9, 2C19, 2D6, 3A (midazolam) and 3A (testosterone) (IC50 values: 
152, 30.0, 13.3, 111, 8.33 and 12.5 μmol/L, respectively) as well as possible time-dependent 
inhibition of CYP3A (midazolam and testosterone).  The time-dependent inhibition of 
CYP3A4 (testosterone) was irreversible, and the in vitro maximum inactivation rate constant 
(kinact) and inhibitor concentrations that gave half-maximal kinact (Ki) values of ASP8273 
were 0.0246 min-1 and 2.12 μmol/L for CYP3A4 (testosterone), respectively. The direct 
inhibitory effects of ASP8273 on CYP1A2, 2C8, 2B6, 2C9, 2C19 and 2D6 were weak, and 
may not be clinically relevant.
An in vitro transcellular transport study using permeability-glycoprotein (P-gp)-expressing 
cells suggested that ASP8273 is a substrate for P-gp-mediated transport. ASP8273 showed an 
inhibitory effect on P-gp-mediated transport of digoxin with an IC50 value of 11.0 μmol/L.
1.2.3
Nonclinical Toxicology
In a single dose toxicity study in rats, the approximate lethal dose level was 500 mg/kg for 
males and females. The main change noted in moribund animals was gastrointestinal 


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hemorrhagic disorder.  In a preliminary single dose toxicity study in dogs, no animals showed 
mortality or moribundity up to 300 mg/kg.
In a 4-week once-daily oral dose toxicity study in rats (0, 3, 10, 30 and 60 mg/kg per day), no 
mortality or moribundity was noted up to 60 mg/kg per day.  The main toxicities observed in 
rats were atrophy of the epithelium in cornea and skin, corneal opacity, atrophy of lymphoid 
tissues, irreversible testicular atrophy (atrophy and dilatation of the seminiferous tubules, 
spermatic granuloma in the testes), alveolar foam cells in the lung, multifocal necrosis of 
hepatocytes, thickening of the epiphyseal cartilage and decreased trabecular bone, and 
vacuolation and foam cell accumulation observed in multiple organs and tissues.  The no 
observed adverse effect level (NOAEL) in rats was < 3 mg/kg per day, as decreased serum 
potassium was noted at 3 mg/kg per day or more.
In a 4-week once-daily oral dose toxicity study in dogs (0, 1.5, 5 and 15 mg/kg per day), 
moribundity was noted at 15 mg/kg per day.  Dosing was discontinued after day 20 and day 
17 for males and females, respectively.  The main organ toxicities in dogs were 
gastrointestinal injury including vomiting and abnormal stool with occult blood, atrophy of 
epithelium in cornea and skin, corneal opacity, atrophy of lymphoid tissues, inflammatory 
cell infiltration, hemorrhage or edema in the alveoli in the lung, dilatation of the distal 
tubules, focal interstitial hemorrhage, and basophilic changes in the proximal tubules in the 
kidney, thickening of the epiphyseal cartilage and decreased trabecular bone, and vacuolation 
and foam cell accumulation observed in multiple organs and tissues. The NOAEL in dogs 
was < 1.5 mg/kg per day as vomiting, decreased erythrocyte parameters, prolonged activated 
partial thromboplastin time (APTT), decreased serum albumin and increased alkaline 
phosphatase (ALP) were observed at doses of ≥ 1.5 mg/kg per day.
Findings in both 4-week studies in rats and dogs were reversible, except for the testicular 
changes in rats (≥ 10 mg/kg per day) and corneal opacity in rats and dogs (rat: ≥ 30 mg/kg 
per day, dog: 15 mg/kg per day), which were observed after a 4-week withdrawal period.  In 
the rat, low lymphocyte and basophil counts in peripheral blood were still noted after a 
4-week recovery period; however, reversibility of these findings are anticipated because 
atrophy in the lymphoid organs and bone marrow hypocellularity did recover.  Based on 
these results, the severely toxic dose in 10% of animals (STD10) in rats was considered to be 
60 mg/kg per day, and the highest nonseverely toxic dose (HNSTD) in dogs was considered 
to be 5 mg/kg per day.
In an ongoing 13-week oral dose toxicity study in the rat (0, 0.3, 3, 10 and 30 mg/kg), a male 
animal from the highest dose group (30 mg/kg) died on day 22 of dosing (8273-TX-0012).  
The cause of death was considered to be treatment related gastrointestinal damage as has 
been previously observed in earlier toxicity studies with ASP8273.
In an embryo fetal development toxicity study in rats (0, 3, 10 and 60 mg/kg per day), 
decreased body weight and food consumption in dams, embryo-fetal death, growth 
retardation and morphological abnormalities were noted at 60 mg/kg per day.  The following 
morphological abnormalities were noted: a tendency to increase in external malformations, 
increases in visceral and skeletal malformations, skeletal variations and ossification findings.  


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The NOAELs were concluded to be 10 mg/kg per day for general toxicity of dams and 
embryo-fetal development.
ASP8273 mesilate did not show genotoxic potential in an in vitro reverse mutation test in 
bacteria. Although numerical chromosomal aberrations were induced in an in vitro 
chromosomal aberration test in mammalian cells, an in vivo micronucleus test in rats at doses 
up to 500 mg/kg per day showed no potential to induce chromosomal aberrations in vivo. 
ASP8273 mesilate showed no potential to induce phototoxicity in cultured mammalian cells.
1.2.4
Clinical Data
ASP8273 mesilate is being evaluated in 3 ongoing studies in NSCLC subjects harboring 
EGFR activating mutation: phase 1/2 Study 8273-CL-0101 (Japan, Korea and Taiwan), a 
phase 1 Study 8273-CL-0102 (US), and a phase 2 Study 8273-CL-0202 (Japan).  Preliminary 
pharmacokinetic data from the 2 studies (8273-CL-0101 and 8273-CL-0102) indicated that 
peak plasma concentrations (Cmax) of ASP8273 were achieved approximately 1 to 6 hours 
after a single dose and at steady state.  ASP8273 exposure (median AUC and Cmax) after 
single and multiple doses increased with dose.  At dose levels of 100 mg to 300 mg, 
ASP8273 exposure was approximately dose-proportional and appeared to be comparable 
between the 2 studies.  
Preliminary data in both ongoing studies noted antitumor activity in the 100 mg and above 
cohorts; 52.4% (22/42), 73.9% (17/23) and 32.7% (18/55) of patients had a partial response 
in Studies 8273-CL-0101 (phases 1 and 2) and 8273-CL-0102, respectively. Preliminary 
safety data is summarized in [Section 1.3.1].
Full details are included in the Investigator’s Brochure, Version 4 [30 July 2015].
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
ASP8273
A total of 170 subjects with NSCLC in ongoing Studies 8273-CL-0101 and 8273-CL-0102 
have received at least 1 dose of ASP8273 mesilate, with dose ranging from 25 mg to 600 mg 
(1 subject received a single dose of 800 mg due to overdose).  The majority of subjects 
experienced at least 1 treatment-emergent adverse event (TEAE).  In ongoing Study 8273-
CL-0101, the 3 most common TEAEs in both studies were diarrhoea, nausea and vomiting; 
and in ongoing Study 8273-CL-0102, the 4 most common TEAEs were diarrhoea, nausea, 
constipation and fatigue.
To date, no subject has died due to an adverse event (AE) in ongoing Study 8273-CL-0101.  
In ongoing Study 8273-CL-0102, 4 subjects experienced TEAEs leading to death (1 subject
each experienced respiratory failure [400 mg group], depressed level of consciousness 
[100 mg group], progression of NSCLC [200 mg group] and multi-organ failure [200 mg 
group]; all of which were considered not related to ASP8273 mesilate by the investigator.  
To date, in ongoing Study 8273-CL-0101, 23 subjects experienced serious AEs (SAEs).  Of
these, 13 subjects experienced SAEs that were considered possibly or probably related to 


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study drug.  The only drug-related SAEs occurring in more than 1 subject were nausea 
(4 events), ALT increased (4 events) and hyponatraemia (2 events).  In ongoing Study 
8273-CL-0102, 19 subjects experienced SAEs.  Of these, 3 subjects experienced SAEs that 
were considered possibly or probably related to study drug (1 event each of nausea [400 mg 
group], pancreatitis [300 mg], hyponatremia [500 mg group] and urinary retention [500 mg 
group]).
To date, 2 subjects from Study 8273-CL-0101 (100 and 600 mg group) and 3 subjects (100, 
200 and 400 mg group) from Study 8273-CL-0102 permanently discontinued due to a TEAE 
(primary reason).  Nausea, vomiting and hyponatremia were the only drug-related TEAEs 
resulting in withdrawal of drug.
In ongoing Study 8273-CL-0101, 9 subjects experienced DLTs (400 mg group, n = 5; 
600 mg group, n = 4).  Diarrhoea was the most common DLT, occurring in 3 subjects.  
Nausea and colitis each occurred in 2 subjects, while the rest of the DLTs occurred in 
1 subject each.  In ongoing Study 8273-CL-0102, 3 subjects in the 400 mg group experienced 
DLTs; they were diarrhea, anorexia and hyponatremia (2 events in 1 subject).
1.3.2
Erlotinib
Detailed information on the toxicities associated with erlotinib can be found within the 
Package Insert (PI), Summary of Product Characteristics (SPC) or local product information.  
Special attention should be paid to the prescribing warnings and precautions for use 
regarding interstitial lung disease (ILD), renal failure, hepatoxocity with or without hepatic 
impairment, gastrointestinal perforation, bullous and exfoliative skin disorders, myocardial 
infarction/ischemia, cerebrovascular accident, microangiopathic hemolytic anemia and 
thrombocytopenia, ocular disorders and embryo-fetal toxicity.  
1.3.3
Gefitinib
Detailed information on the toxicities associated with gefitinib can be found within the 
Package Insert (PI), Summary of Product Characteristics (SPC) or local product information.  
Special attention should be paid to the prescribing warnings and precautions for use 
regarding ILD, hepatoxocity and liver impairment, interactions with other medicinal products, 
lactose, gastrointestinal perforation, keratitis, increased INR in patients taking warfarin, and 
severe or persistent diarrhea, nausea, or anorexia that may lead to dehydration.  
1.4
Risk-Benefit Assessment
ASP8273 has been administered in 2 NSCLC tumor-specific phase 1/2 studies to date.  
Across these 2 studies preliminary data suggest antitumor activity with ASP8273 in subjects 
with advanced NSCLC harboring EGFR activating mutations previously treated with an 
EGFR TKIs, primarily in subjects with known T790M positive mutation status or their 
mutation status is unknown.  This early antitumor activity is consistent with the nonclinical 
data that suggested that ASP8273 may have antitumor activity in patients with NSCLC 
harboring EGFR activating mutations with or without the T790M resistance mutation.  Hence, 
this may be a potential benefit for such patients to receive ASP8273.


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Additionally, erlotinib and gefitinib are both approved and have demonstrated effectiveness 
in treating subjects with NSCLC harboring certain activating mutations of EGFR.
The potential undesirable effects in humans based on toxicities observed in the nonclinical 
studies with ASP8273 are summarized in [Section 1.3]. The most common AEs from the 
initial safety observations in the 2 ASP8273 phase 1/2 studies to date include diarrhea, 
nausea, vomiting, constipation and fatigue.  The increased frequency and severity of these 
events appear to occur in a dose dependent manner. 
The initial safety observations from these trials are consistent with the preclinical findings 
and other approved EGFR TKI therapies. Therefore, the possible benefits of antitumor 
activity in subjects taking ASP8273 therapy appear to outweigh potential risks in this patient 
population.  See the current ASP8273 Investigator’s Brochure for full list of TEAEs.
Erlotinib and Gefitinib both have well-characterized safety profiles with acceptable 
management of AEs in the clinical setting.
The current safety monitoring plan is designed to monitor for EGFR class related toxicities 
including laboratory values and physical exam findings and contains detailed dose reduction 
management guidelines specific to these types of AEs.  Strict adherence to the schedule of 
safety assessments to ensure that patients receive adequate safety monitoring is essential.  
Equally important, strict adherence to the eligibility criteria is essential to ensure that 
appropriate patients are selected for participation. In addition, an IDMC will be formed to 
review safety data on a regular basis to ensure patient safety.
The overall risk-benefit assessment for this patient population appears favorable.
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
●
To evaluate the progression free survival (PFS), based on independent radiologic review
(IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, 
metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer 
(NSCLC) with EGFR activating mutations
2.1.2
Secondary Objectives
●
Overall survival (OS)
●
Overall response rate (ORR) as assessed by IRR
●
PFS as assessed by the investigator
●
Disease control rate (DCR) as assessed by IRR
●
Duration of Response (DOR) as assessed by IRR
●
Safety of ASP8273
●
To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) parameters as 
measured by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-QLQ-C30 and EQ-5D-5L


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2.1.3
Exploratory Objectives
●
To evaluate potential biomarkers that may affect treatment outcome
●
Evaluation of the pharmacokinetics of ASP8273
●
To evaluate the impact of subsequent therapy on progression free survival on next-line 
therapy (PFS#2)
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This multinational, open-label randomized study will evaluate ASP8273 compared to 
erlotinib or gefitinib (1st generation EGFR TKI) as first line therapy in subjects with locally 
advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma NSCLC (newly 
diagnosed or recurrent) with EGFR activating mutations (exon 19 deletion or exon 21 
L858R), with or without a T790M mutation, who have not previously been treated with an 
EGFR inhibitor (1st line).
PFS by IRR is the primary variable.  Secondary variables include OS, ORR, PFS by the 
investigator, DCR, DOR, safety and QoL/PRO.  Exploratory variables include biomarkers, 
pharmacokinetics and PFS#2 on subsequent therapy.
Approximately 600 subjects will be randomized 1:1 to 1 of 2 treatment arms (Arm A or 
Arm B).  Arm A will receive 300 mg daily of ASP8273 and Arm B will receive either 
150 mg erlotinib or 250 mg gefitinib daily, as decided by the investigator for each site at the 
beginning of the trial.  Both arms will follow 28-day cycles of continuous dosing.  Subjects 
will be stratified according to the following:  ECOG PS (0, 1 or 2), EGFR mutation status 
(exon 19 deletion or mutations in exon 21 [L858R]), TKI chosen (erlotinib or gefitinib) and 
race (Asian versus non-Asian).
Screening will take place up to 28 days prior to subject randomization on cycle 1 day 1.  
Subjects will start with cycle 1 and continue on to subsequent 28-day cycles until 1 of the 
discontinuation criteria are met.  Subjects will visit the clinic for evaluations on day 1 and 
day 15 of treatment cycle 1 and then on day 1 of subsequent treatment cycles up to cycle 7.  
Subjects who continue past cycle 7 will have visits on day 1 of each odd-numbered cycle.  
Quality of life will be assessed during each treatment cycle where a visit takes place, at the 
follow-up visit, and at each of the posttreatment or long-term follow-up survival contacts for 
6 months after treatment discontinuation (EQ-5D-5L only).
Imaging will be evaluated at baseline and every 56 days (± 7 days) throughout the study.  
Imaging of the brain is required at baseline for all subjects, and may be repeated throughout 
the study as clinically indicated.  If a brain lesion not previously irradiated is selected as a 
target lesion at baseline, the assessment should be repeated at all subsequent imaging 
timepoints.  A blinded independent central reader will review all imaging scans to confirm 
complete response (CR), partial response (PR), stable disease (SD) or progressive disease 
(PD) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. Disease progression 


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on study drug (PFS#1) should be confirmed by the blinded independent central reader before 
subjects are discontinued from treatment.  
Following discontinuation from study drug, subjects will have a follow-up visit 30 days (+7 
days) after their last dose of drug for safety assessments. If a subject discontinues study drug 
prior to radiographic disease progression (i.e., PFS#1), the subject should enter the 
posttreatment follow-up period and continue to undergo imaging assessments every 56 days 
(+/- 7 days) until PFS#1 is documented or the subject starts another anticancer treatment, 
whichever occurs earlier. 
Following PFS#1, subjects will enter the long-term follow-up period and be followed every 
3 months from the date of the follow-up visit for survival status and progression status on 
subsequent therapy (i.e., PFS#2). Subjects will be followed until PFS#2 is documented or the 
subject starts another anticancer treatment, whichever occurs earlier.  All subsequent 
anticancer therapy including date and site of progression for PFS#2 will be recorded on the 
case report form.  
Following PFS#2, subjects will enter the survival follow-up period and be followed every 
3 months for survival status. 
Samples for pharmacokinetics, biomarkers and pharmacogenomics (PGx) as well as formalin 
fixed paraffin embedded (FFPE) specimens for central analysis will be collected. Eligibility 
may be determined by a previously documented EGFR mutation result. However, there 
should be sufficient tissue from the specimen used to generate the EGFR test result to send to 
the central lab for confirmatory testing. If a subject does not have a previously documented 
EGFR mutation test result, then a fresh specimen must be obtained and sent to the central lab 
for eligibility testing. An optional post-progression tumor tissue sample for exploratory 
analysis of biomarkers (e.g., EGFR mutation [T790M, C797S], c-Met mutation/amplification 
and AXL over expression), which are potentially related to EGFR-TKI drug response or 
resistance, may be collected following locally or centrally confirmed disease progression for 
subjects who sign a separate informed consent form (ICF).  
An independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and 
the planned futility analysis which will occur after at least 210 PFS events have been observed.  
The primary analysis will occur when at least 420 PFS#1 events are observed which is 
expected to occur approximately 36 months after randomization of the first subject. Primary 
endpoint, secondary endpoints and other endpoints will be analyzed at the time of primary 
analysis.
2.2.2
Dose Rationale
A once daily treatment of 300 mg has been selected as the recommended starting dose based 
on the relative balance between antitumor effect and toxicity observed in the phase 1 dose 
escalation studies (8273-CL-0101 and 8273-CL-0102).  Although the 300 mg and 400 mg 
dose cohorts appear to have comparable preliminary antitumor activity, there were fewer 
DLTs noted at 300 mg as compared to 400 mg. In the phase 1/2 study in Japan (8273-CL-
0101), the MTD for ASP8273 was established as 400 mg utilizing a Bayesian continual 


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reassessment methodology.  In the phase 1 study in the US (8273-CL-0102), the MTD for 
ASP8273 has not yet been established, but estimated to be > 500 mg utilizing a similar 
Bayesian continual reassessment methodology.  Based on the differential affinities for 
activating EGFR mutations relative to wild-type EGFR for ASP8273, dosing at the MTD is 
not necessarily required for antitumor activity, whereas the MTD is likely related to 
wild-type EGFR related toxicities. Of note, DLTs were observed in the 400 mg cohort of 
both phase 1 studies, and clinical antitumor responses were noted in dose levels of 100 mg 
and above in both studies.
Erlotinib and gefitinib are both approved for the treatment of NSCLC and the starting doses 
selected are consistent with current product labeling.
2.3
Endpoints 
2.3.1
Primary Endpoints
●
PFS as assessed by IRR 
2.3.2
Secondary Endpoints 
●
OS
●
Best overall response rate (CR + PR) by IRR
●
PFS by the investigator
●
Disease control rate (CR+PR+SD) by IRR
●
DOR by IRR
●
Safety variables (e.g., AEs, laboratory tests, vital sign measurements, ECGs)
●
QoL and PRO parameters
2.3.3
Exploratory Endpoints
●
Plasma T790M and other biomarkers related to EGFR TKI sensitivity and/or resistance
●
Plasma pharmacokinetics of ASP8273
●
PFS#2 on subsequent therapy
3
STUDY POPULATION
3.1
Selection of Study Population 
First-line subjects with locally advanced, metastatic or unresectable stage IIIB/IV 
adenocarcinoma NSCLC (newly diagnosed or recurrent) with EGFR activating mutations 
(exon 19 deletion or exon 21 L858R) will be selected for this study. Subjects who have both an 
exon 19 deletion and exon 21 L858R mutation will not be included.
3.2
Inclusion Criteria
Subject must meet all of the following inclusion criteria to be eligible for participation in this 
study at enrollment:


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1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., HIPAA 
Authorization for U.S. sites) must be obtained from the subject or legally authorized 
representative prior to any study-related procedures.
2.
Subject is ≥ 18 years of age and legally an adult according to local regulation at the time 
of signing informed consent.
3.
Subject agrees not to participate in another interventional study while on treatment.
4.
Female subject must either:
●
Be of nonchildbearing potential:
o
postmenopausal (defined as at least 1 year without any menses) prior to 
Screening, or 
o
documented surgically sterile
●
Or, if of childbearing potential:
o
Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration
o
And have a negative serum pregnancy test at Screening 
o
And, if heterosexually active, agree to consistently use 2 forms of birth 
control* (at least 1 of which must be a highly effective method* and one must 
be a barrier method) starting at Screening and throughout the study period and 
for 28 days after the final study drug administration
5.
Female subject must not be breastfeeding at Screening or during the study period, and 
for 28 days after the final study drug administration.
6.
Female subject must not donate ova starting at Screening and throughout the study 
period, and for 28 days after the final study drug administration.
7.
Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (1 of which 
must be a barrier method) starting at Screening and continue throughout the study period 
and for 90 days after the final study drug administration.
*Highly effective forms of birth control include:
●
Consistent and correct usage of established oral, injected or implanted hormonal 
methods of contraception
●
Established intrauterine device (IUD) or intrauterine system (IUS)
*Acceptable methods of birth control include:
●
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (not 
applicable in Japan and Thailand: with spermicidal 
foam/gel/film/cream/suppository)
●
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method [Japan 
and Thailand only])


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8.
Male subject must not donate sperm starting at Screening and throughout the study 
period and for 90 days after the final study drug administration.
9.
Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
10. Subject has histologically confirmed locally advanced, metastatic or unresectable Stage 
IIIB/IV adenocarcinoma NSCLC (newly diagnosed or recurrent).  Subjects with mixed 
histology are eligible if adenocarcinoma is the predominant histology.
11. Subject has predicted life expectancy 12 weeks in the opinion of the investigator.
12. Subject must meet all of the following criteria on the laboratory tests that will be 
analyzed centrally within 7 days prior to the first dose of study drug.  In case of multiple 
laboratory data within this period, the most recent data should be used.
●
Neutrophil count > 1,000/mm3
●
Platelet count 7.5 104 /mm3
●
Hemoglobin > 8.0 g/dL
●
Serum creatinine 2.0 x ULN or an estimated glomerular filtration rate (eGFR) of 
> 50 mL/min as calculated by the Cockcroft Gault Method
●
Total bilirubin 1.5 ULN (except for subjects with documented Gilbert’s 
syndrome)
●
AST and ALT 3.0 ULN or ≤ 5 ULN if subject has documented liver 
metastases
●
Serum sodium level is ≥130 mmol/L
13. Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or 
without T790M mutation, by local or central testing on examination of a NSCLC FFPE 
specimen (archival or fresh biopsy). Subjects harboring both exon 19 deletion and exon 
21 L858R mutations are not eligible.  A tissue sample from the same block used to 
determine eligibility by local testing should be available to send to the central lab for 
confirmatory testing.  Subjects randomized based on local results indicating presence of 
EGFR mutation may remain on study if central results are discordant.
14. Subject must have at least 1 measureable lesion based on RECIST V1.1.  Previously 
irradiated lesions will not be considered as measurable lesions.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible 
for enrollment:
1.
Subject has received intervening anticancer treatment or previous treatment with 
chemotherapy for metastatic disease other than palliative local radiation to painful bone 
metastases completed at least 1 week prior to the first dose of study drug.  The
administration of neoadjuvant or adjuvant chemotherapy is allowed as long as it has 
finalized ≥ 6 months before the first dose of study drug. 


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2.
Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., 
afatinib, dacomitinib, ASP8273, etc).
3.
Subject has received investigational therapy within 28 days or 5 half-lives prior to the 
first dose of study drug.
4.
Subject has received radiotherapy within 1 week prior to the first dose of study drug.  If 
the subject received radiotherapy > 1 week prior to study treatment, the irradiated lesion 
cannot be the only lesion used for evaluating response.
5.
Subject has symptomatic central nervous system (CNS) metastasis.  Subject with 
previously treated brain or CNS metastases are eligible provided that the subject has 
recovered from any acute effects of radiotherapy, does not have brain metastasis related 
symptoms, is not requiring systemic steroids for at least 2 weeks prior to study drug 
administration, and any whole brain radiation therapy was completed at least 4 weeks 
prior to study drug administration or any stereotactic radiosurgery (SRS) was completed 
at least 2 weeks prior to study drug administration. Steroid inhaler use or ointment 
treatment for other concomitant medical disease is permitted.
6.
Subject has received blood transfusions or hematopoietic factor therapy within 14 days 
prior to the first dose of study drug.
7.
Subject has had a major surgical procedure (other than a biopsy) within 14 days prior to 
the first dose of study drug, or one is planned during the course of the study. 
8.
Subject has a known history of a positive test for human immunodeficiency virus (HIV) 
infection.
9.
Subject has known history of serious hypersensitivity reaction to a known ingredient of 
ASP8273, erlotinib or gefitinib.
10. Subject has evidence of an active infection requiring systemic therapy within 14 days 
prior to the planned first dose of study drug.
11. Subject has severe or uncontrolled systemic diseases including uncontrolled 
hypertension (blood pressure > 150/100 mmHg) or active bleeding diatheses.
12. Subject has history of drug-induced ILD or any evidence of active ILD.
13. Subject has ongoing cardiac arrhythmia that is Grade ≥2 or uncontrolled atrial 
fibrillation of any grade. 
14. Subject currently has Class 3 or 4 New York Heart Association congestive heart failure.
15. Subject has history of severe/unstable angina, myocardial infarction or cerebrovascular 
accident within 6 months prior to the planned first dose of study drug.
16. Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months 
prior to the planned first dose of study drug.


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17. Subject has concurrent corneal disorder or any ophthalmologic condition which, in the 
investigator’s opinion, makes the subject unsuitable for study participation (i.e., 
advanced cataracts, glaucoma).
18. Subject has difficulty taking oral medication or any digestive tract dysfunction or 
inflammatory bowel disease that would interfere with the intestinal absorption of drug.
19. Subject has another past or active malignancy which requires treatment.  Prior carcinoma 
in situ or non-melanoma skin cancer after curative resection are permitted.
20. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation. 
21. Subject has received potent CYP 3A4 inhibitors within 7 days prior to first dose of study 
drug or proton pump inhibitors such as omeprazole within 14 days prior to first dose of 
study drug.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
ASP8273 will be provided as oral capsules in 100 mg strength packaged in HDPE bottles with 
child resistant cap and dessicant, containing 30 capsules each. ASP8273 should be stored at 
20C to 25C (68-77F) with excursions permitted to 15to 30C (59-86F). Additional 
information regarding ASP8273 can be found in the ASP8273 Investigator’s Brochure.
4.1.2
Comparative Drug(s) 
Erlotinib will be provided as oral tablets in 150, 100 and 25 mg strengths in bottles containing 
30 tablets each. Erlotinib should be stored at room temperature, 25C (77F) with excursions 
permitted to 15to 30C (59-86F).
Gefitinib will be provided as oral tablets in 250 mg strength in blister packs containing 
30 tablets each. Gefitinib should be stored at room temperature between 1C and 30C 
(33.8-86F).
Comparative drugs will be provided by the study sponsor; however, should sponsor supplies 
become unavailable, site supplies may be used with prior approval from sponsor.  
4.2
Packaging and Labeling
All medication provided by the sponsor in this study will be prepared, packaged, and labeled 
under the responsibility of qualified staff APGD-AUST or sponsor’s designee in accordance 
with  APGD-AUST or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local 
laws/regulations.


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Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations which identifies the contents as investigational drug.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and
●
that such deliveries are recorded,
●
that study drug is handled and stored according to labeled storage conditions,
●
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
that any unused study drug is returned to the sponsor.
Drug inventory and accountability records for the study drugs will be kept by the investigator/
or designee. Study drug accountability throughout the study must be documented and 
reconciled. The following guidelines are therefore pertinent:
●
The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the investigator or designee.  The 
inventory will include details of material received and a clear record of when they were 
dispensed and to which subject.
●
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented.  Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site must return study drug to the sponsor or designee at the end of the study or upon 
expiration.
4.4
Blinding
This section is not applicable as this is an open-label study. 
4.5
Assignment and Allocation
Randomization in a 1:1 ratio to each of the 2 treatment arms will be performed via Interactive 
Response Technology (IRT).  Randomization will be stratified by ECOG PS (0, 1 or 2), 
EGFR mutation type (exon 19 deletion or mutation in exon 21 L858R), TKI chosen (erlotinib 
versus gefitinib) and race (Asian versus nonAsian).  At the beginning of the trial, prior to site 
initiation and shipment of study drug supplies, each investigator will select either erlotinib or 
gefitinib to be utilized for all patients randomized to the comparator arm at their site.  Prior to 


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the initiation of the study treatment, the site staff will contact the IRT in order to determine 
the randomly assigned treatment arm.  Specific procedures for randomization through the 
IRT are contained in the study procedures manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
ASP8273 300 mg and erlotinib 150 mg will be taken orally once daily, on an empty stomach 
defined as no food for at least 2 hours before and 1 hour after dosing, at approximately the 
same time(s) every day. 
Gefitinib 250 mg will be taken orally once daily, with or without food, at approximately the 
same time every day.
Concomitant medications should not be administered within 2 hours before or after dosing 
with ASP8273, erlotinib or gefitinib.
If a study drug dose is missed, it should be taken as soon as the subject remembers unless 
more than 12 hours has passed since the intended dosing time, in which case the subject 
should wait and take the next scheduled dose.  Subjects should not make up a missed dose by 
taking a double dose at the next scheduled dose.
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
Dosing for ASP8273, erlotinib or gefitinib may be interrupted for any event if the investigator 
deems it necessary to ensure subject safety.  Dosing for ASP8273 or erlotinib may be reduced 
if necessary.  Subjects requiring a treatment interruption should be re-evaluated not longer than 
7 days from initial interruption and restarted on study drug as soon as clinically stable.  The 
subject may be discontinued from treatment if there is an interruption of treatment for > 14 
consecutive days despite optimal treatment of side effects.  A discussion with the Medical 
Monitor should occur to confirm if the subject should continue on study treatment.
In the event of acute onset or worsening of pulmonary symptoms likely suggestive of ILD
(dyspnea, cough, fever), study drug should be interrupted and a prompt investigation of these 
symptoms should occur and appropriate treatment initiated.  If ILD is confirmed, study drug 
should be discontinued, and the subject should be treated appropriately per local standard of 
care.
Study drug should be interrupted if the subject experiences eye toxicity such as acute and 
severe eye pain or keratitis.  Subjects with suspected keratitis should have study drug withheld 
until recovery and discontinued for persistent severe keratitis.  Subjects with ocular toxicities 
should be evaluated by an ophthalmologist.  


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If the subject experiences severe hepatic impairment, study drug should be discontinued and 
the subject should be treated appropriately per local standard of care.
5.1.2.1 ASP8273 Dose Modification
Subjects requiring a dose reduction may be re-escalated one dose level (i.e., subjects reduced to 
100 mg may only be re-escalated to 200 mg).  If the event leading to the reduction recurs, the 
subject should be reduced to the lower dose level and not re-escalated again. If a grade 3 or 4 
study drug-related toxicity persists, or recurs after 2 dose reductions, the subject will be 
permanently discontinued from ASP8273 treatment. Additionally, if after resolution of a Grade 
4 event (except diarrhea, nausea and vomiting) requiring dose interruption and/or dose 
reduction, the event reoccurs at a G3 or higher the subject should be permanently discontinued 
from ASP8273.
Table 3
ASP8273 Dose Modification
Dose level
ASP8273 dose (mg qd)
Starting dose
300
-1
200
-2
100
Table 4
Events Requiring ASP8273 Dose Modification
ASP8273 Dose Modification Criteria
Diarrhea, nausea, vomiting 
Grade 1

Continue at same dose
Grade 2

Continue at same dose if tolerable and manage as clinically indicated at the 
discretion of the investigator
Grade 3 or 4

Interrupt dosing until the AE is managed to Grade ≤ 1 or baseline, then resume 
treatment at the same dose

If the AE recurs at Grade ≥3 when the same dose is resumed, then interrupt 
dosing until the AE is managed to Grade ≤ 1 or baseline, then resume treatment 
1 dose level lower
Neuropathy 
Grade 1

Continue at same dose
Grade 2

Interrupt dosing at the discretion of the investigator until AE recovers to ≤Grade 1 
or baseline and resume treatment at the same dose.  Investigate etiology of the 
neuropathy at the discretion of the investigator

If Grade 2 recurs after resuming study drug, reduce treatment to 1 dose level lower
Grade 3

Interrupt dosing until the AE recovers to ≤ Grade 1 or baseline.  Investigate 
etiology of the neuropathy at the discretion of the investigator

Dosing may be resumed, at the discretion of the investigator, 1 dose level lower

If Grade ≥ 3 recurs after resuming study drug, discontinue study drug permanently
Grade 4

Permanently discontinue study drug and manage as clinically indicated at the 
discretion of the investigator
Table continued on next page


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ASP8273 Dose Modification Criteria
Hyponatremia
Grade 1

Recheck serum sodium levels as clinically indicated

In addition, urine osmolality, serum osmolality, and urine sodium concentrations 
should also be measured as clinically indicated

Dosing may continue without interruption at the discretion of the investigator
Grade 2
Not defined by NCI CTCAE v4.3
Grade 3

For serum sodium levels < 130 – 125 mmol/L dosing may continue at the 
discretion of the investigator with additional monitoring as noted below

For serum sodium levels < 125 mm/L interrupt dosing

Serum sodium levels, serum osmolality, urine osmolality and urine sodium 
concentrations should be measured to determine the etiology of the hyponatremia 
and continue to be drawn as clinically indicated until the serum sodium levels 
recover ≤ Grade 1 or baseline

Consider fluid management plan if clinically indicated at the discretion of the 
investigator

Dosing should be held until serum sodium levels recover to ≤ Grade 1 or baseline, 
then dosing my resume, at the discretion of the investigator, at 1 dose level lower

If Grade 3 hyponatremia recurs after resuming ASP8273 at a reduced dose, 
ASP8273 may be discontinued
Grade 4

Interrupt dosing immediately 

Consider intravenous infusion of hypertonic saline, fluid management, or other 
management plan as clinically indicated at the discretion of the investigator

Serum sodium levels, serum osmolality, urine osmolality and urine sodium 
concentrations should be measured to determine the etiology of the hyponatremia 
and continue to be drawn as clinically indicated until the serum sodium levels
recover ≤ Grade 1 or baseline

Correct sodium level at appropriate correction rate to avoid the risk of central 
pontine myelinolysis

Dosing should be held until serum sodium levels recover to ≤ Grade 1 or baseline, 
then treatment may resume, at the discretion of the investigator, at 1 dose level 
lower

If Grade ≥ 3 hyponatremia recurs after resuming drug at a reduced dose 
discontinue ASP8273
Table continued on next page


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ASP8273 Dose Modification Criteria
AST or ALT Elevation1
Grade 3

Interrupt dosing until the AE recovers to grade ≤ 1 or baseline, then resume 
treatment at the same dose level or 1 dose level lower at the discretion of the 
investigator

If Grade ≥ 3 AST or ALT elevation recurs after resuming study drug at the same 
dose level, an additional rechallenge at a reduced dose may be considered, at the 
discretion of the investigator, once the AE recovers to grade ≤ 1 or baseline.  If 
Grade ≥ 3 AST or ALT elevation recurs after resuming study drug at a reduced 
dose, discontinue study drug
Grade 4

Interrupt dosing until the AE recovers to grade ≤ 1 or baseline

At the discretion of the investigator, either discontinue study drug or resume study 
drug 1 dose level lower

If Grade ≥ 3 AST or ALT elevation recurs after resuming study drug at a reduced 
dose, discontinue study drug
Interstitial Lung Disease
Any grade

If ILD is suspected, ASP8273 should be interrupted immediately pending 
diagnostic evaluation.  If ILD is diagnosed, ASP8273 should be discontinued 
permanently and appropriate treatment instituted as necessary.
Other adverse events, including ocular toxicity
Grade 3

Interrupt dosing until the AE recovers to grade ≤ 1 or baseline, then resume 
treatment at the same dose level or 1 dose level lower at the discretion of the 
investigator

If Grade ≥ 3 AE recurs after resuming study drug at the same dose, an additional 
rechallenge at a reduced dose may be considered, at the discretion of the 
investigator, once the AE recovers to grade ≤ 1 or baseline

If Grade ≥ 3 AE recurs after resuming study drug at a reduced dose, discontinue 
study drug
Grade 4

Interrupt dosing until the AE recovers to grade ≤ 1 or baseline

At the discretion of the investigator, either discontinue study drug or resume study 
drug 1 dose level lower

If Grade ≥ 3 AE recurs after resuming study drug at a reduced dose, discontinue 
study drug
1
Hold ASP8273 and repeat AST and ALT within 1 day to confirm abnormal results before discontinuing 
subject from ASP8273 treatment.
5.1.2.2 Erlotinib Dose Modification
Table 5
Erlotinib Dose Modification
Dose level
Erlotinib (mg qd)
Starting dose
150
-1
100
-2
50


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Dose modifications for erlotinib are suggested for toxicities of ILD, skin rash, and diarrhea, 
however the locally approved label for erlotinib dose modification for toxicities should be 
followed. Subjects requiring dose reduction of erlotinib may have the dose re-escalated if 
they have been on a stable dose for ≥ 3 weeks without further toxicities requiring dose 
modification and it is considered by the investigator to be in the best interest of the subject. If 
any toxicity requiring dose interruption of erlotinib recurs despite the initial dose reduction to 
level -1 (100 mg qd), erlotinib may be reduced again to level -2 (50 mg qd). If 2 levels of 
erlotinib dose reduction are required, subsequent reescalation may only be to dose level -1.
Treatment with erlotinib should be used with extra caution in subjects with total bilirubin
> 3 x ULN. Erlotinib dosing should be interrupted or discontinued if changes in liver function
are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of
pretreatment values outside normal range. In the setting of worsening liver function tests,
before they become severe, dose interruption and/or dose reduction with frequent liver
function test monitoring should be considered. Erlotinib dosing should be interrupted or
discontinued if total bilirubin is > 3 x ULN and/or transaminases are > 5 x ULN in the setting
of normal pretreatment value.
Table 6
Events Requiring Erlotinib Dose Modification
Erlotinib Dose Modification Criteria
Toxicity
(NCI CTCAE v4.03)
Dose Modification1 for Erlotinib
Diarrhea
Grade 1 or 2
None.  Initiate therapy with antidiarrhea medication as needed
Grade 32 or 42
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower
Rash
Grade 1
None 
Grade 2
None.  If rash persists and is intolerable or worsens over 10-14 days, then reduce by 
1 dose level and initiate treatment as outlined in protocol.
Grade 32
Reduce by 1 dose level.  If rash persists or worsens over 10-14 days, then interrupt 
erlotinib until resolution to grade 2 and then restart 1 dose level lower.
Grade 4
Permanently discontinue erlotinib
Interstitial Lung Disease
Any Grade
If ILD is suspected, erlotinib should be interrupted immediately pending diagnostic 
evaluation.  If ILD is diagnosed, erlotinib should be discontinued permanently and 
appropriate treatment instituted as necessary.
Other Toxicities, including ocular toxicity
Grade 1 or 2
None
Grade 3 2, 3
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower
Grade 4
Permanently discontinue erlotinib
Footnotes appear on next page


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1
Doses that have been reduced to 100 mg/day may be reescalated to 150 mg/day, but only if the toxicity that 
led to the dose reduction has abated or returned to baseline severity, and the investigator believes it is in the 
best interest of the subject.  Doses that have been reduced to 50 mg/day may be reescalated to 100 mg/day, 
but only if the toxicity that led to the dose reduction has abated or returned to baseline severity, and the
investigator believes it is in the best interest of the subject.  Doses that have been reduced to 50 mg/day 
may never be re-escalated to a dose higher than 100 mg/day.  Any subject who fails to tolerate treatment 
with 50 mg/day will be discontinued from erlotinib and enter the posttreatment period of the study.
2
If the event does not resolve to grade 2 by 14 days, erlotinib will be discontinued.
3
Only if 2 grade level change from baseline
5.1.2.3 Gefitinib Dose Modification
There will be no dose reductions for subjects receiving gefitinib as it is only available as a 
single strength tablet. Below summarizes recommended therapy interruption for gefitinib; 
however, the locally approved label should be followed for additional guidance.
Gefitinib Dose Modification Criteria
Toxicity
(NCI CTCAE v4.03)
Dose Modification for Gefitinib
Diarrhea
Persistent Grade 
2 or ≥ Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to Grade 
≤ 1or baseline.
Skin Reactions
Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to Grade 
≤ 1or baseline.
Interstitial Lung Disease
Any Grade
In the event of acute onset or worsening of pulmonary symptoms suggestive of 
ILD (dyspnea, cough fever), gefitinib should be interrupted immediately 
pending diagnostic evaluation.  If ILD is confirmed, gefitinib should be 
discontinued permanently and appropriate treatment instituted as necessary.
AST, ALT or bilirubin elevation
Grade 2
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to Grade 
≤ 1or baseline.
Other Toxicities, including ocular toxicity 
Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to Grade 
≤ 1or baseline.
If ILD, persistent severe keratitis, severe hepatic impairment or gastrointestinal perforation is 
confirmed, gefitinib should be discontinued, and the subject should be treated appropriately 
per local standard of care.
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication Therapy)
All medications and concomitant treatments administered from 28 days prior to cycle 1 day 1 
must be recorded in the eCRF. Documentation will include the medication name, indication, 
route and dates of administration. 


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Arm A (ASP8273)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
1
Chemotherapy, radiotherapy, immunotherapy, or other 
medications intended for antitumor activity 
Likely affect efficacy, safety or 
pharmacokinetics of ASP8273
2
Investigational products or therapy other than ASP8273
3
Potent inhibitors (e.g., ketoconazole, grapefruit or 
grapefruit juice) or inducers (e.g., rifampin, phenytoin or 
St. John’s wort) of CYP3A4 
ASP8273 is a substrate of CYP3A4 
4
CYP3A4 and/or P-gp substrates with a narrow 
therapeutic index1
ASP8273 may be an inhibitor of 
CYP3A4 and/or P-gp
1
The drugs defined as CYP Substrates with Narrow Therapeutic Range by FDA’s guidance - Guidance for 
Industry Drug Interaction Studies - Study Design, Data analysis, and Implications for Dosing and Labeling): 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.
pdf)
The use of the following medications should be avoided or used with caution and closely
monitored.
Medications to be Avoided or Used with Caution
Reason to be Cautious
1
Moderate/weak inhibitors or inducers of CYP3A4 
ASP8273 is a substrate of CYP3A4 
2
Inhibitors or inducers of P-gp
ASP8273 is a substrate of P-gp
3
CYP3A4 and/or P-gp substrates 
ASP8273 may be an inhibitor of 
CYP3A4 and/or P-gp
Arm B (Erlotinib/Gefitinib)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of erlotinib/gefitinib, and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
All Subjects
Chemotherapy, radiotherapy, 
immunotherapy, or other medications 
intended for antitumor activity other than
erlotinib/gefitinib
Likely affect efficacy, safety or 
pharmacokinetics of erlotinib or 
gefitinib
Investigational products or therapy
Potent inhibitors (e.g., ketoconazole,
grapefruit or grapefruit juice) or inducers 
(e.g., rifampin, phenytoin or St. John’s 
wort) of CYP3A4 
Erlotinib and gefitinib are substrates 
of CYP3A4
Proton pump inhibitors or drugs that 
cause significant elevation in gastric pH
Elevation in gastric pH may reduce 
bioavailability of erlotinib or 
gefitinib


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The use of the following medications should be avoided or used with caution and closely
monitored:
Medications to be Avoided or Used with Caution
Reason to be Cautious
All Subjects
Moderate/weak inhibitors or inducers of 
CYP3A4
Erlotinib and gefitinib are substrates 
of CYP3A4
Inhibitors or inducers of P-gp
Erlotinib and gefitinib are substrates 
of P-gp
Warfarin
INR elevations and/or bleeding 
events have been noted in subjects 
taking warfarin while on erlotinib and 
gefitinib therapy
Subjects 
receiving 
erlotinib
Potent inhibitors of CYP1A2
Erlotinib is a substrate of CYP1A2
Subjects 
receiving 
gefitinib
Potent inhibitors of CYP2D6
Gefitinib is a substrate of CYP2D6
CYP2D6 substrates with narrow 
therapeutic index1
Gefitinib is an inhibitor of CYP2D6
1 The drugs defined as CYP Substrates with Narrow Therapeutic Range by FDA’s guidance - Guidance for 
Industry Drug Interaction Studies - Study Design, Data analysis and Implications for Dosing and Labeling): 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM29
2362.pdf)
5.1.4
Treatment Compliance
The dose of ASP8273 or erlotinib/gefitinib administered to each subject will be recorded on 
the subject diary and entered in to the eCRF.  Reasons for dose interruption, reduction or 
omission will also be recorded.  This information, plus study drug accountability at every 
cycle will be used to assess compliance with the treatment. 
Any subject who misses > 14 consecutive days of study drug dosing, on either treatment arm, 
may be discontinued from the study upon discussion between the investigator and sponsor’s 
Medical Monitor.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information will be collected for all subjects and will include initials (where 
allowed), date of birth, sex, race, ethnicity and tobacco use history (pack years).
5.2.2
Medical History
Medical history includes all significant medical conditions other than NSCLC that have 
resolved prior to informed consent or are ongoing at the time of consent.  Details that will be 
collected include the onset date and recovery date and CTCAE grade, if applicable for 
ongoing conditions. 


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5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A complete medical history of the target disease will be recorded at Screening.  This will 
include:
●
NSCLC diagnosis (date and method of diagnosis, including dates of diagnostic 
procedures)
●
TNM classification and disease stage at screening
●
EGFR mutation status and method used to determine status (e.g., sequencing or PCR-
based assay)
●
Dates and type of previous therapy or surgery for NSCLC
●
Other disease-specific information as designated in the eCRF
5.2.4
Performance Status
The ECOG Scale [Oken, 1982] will be used to assess performance status. Refer to 
[Appendix 12.10].
5.3
Efficacy Assessment
Response and progression will be evaluated in this study using RECIST V1.1 (see 
[Appendix 12.9]).  
Imaging will be performed and assessed at Screening (baseline) and every 56 days (± 7 days)
throughout the study. Imaging of the brain is required at baseline for all subjects, and may be 
repeated throughout the study as clinically indicated. If a brain lesion not previously irradiated
is selected as a target lesion at baseline, the assessment should be repeated at all subsequent 
imaging timepoints. Scans should be scheduled in such a way to allow for the results to be 
available for the day 1 visit of each odd cycle (cycle 3, 5, 7 etc). Baseline imaging performed 
prior to informed consent as standard of care may be used so long as it is performed within 
28 days prior to randomization and will meet the comparability requirements outlined below.
Scans will be read on site and also submitted in digital format for blinded independent central 
review until PFS#1 has been confirmed for each subject.  
CT scan with contrast (chest and abdomen) is the preferred modality for tumor assessment.  
MRI is acceptable if local standard practice, or CT scans are contraindicated in a subject 
(e.g., subject is allergic to contrast media).  All other RECIST-approved scanning methods 
such as x-ray are optional. PET-CT scans must use contrast. Additional instructions for 
imaging assessments can be found in the study procedures manual.
The assessment will include tumor measurements for target lesions, non-target lesions and 
any new lesions.An overall assessment will be characterized for a given time point
evaluation. At the end of study for that subject, the best overall response to the study regimen 
will be characterized. To ensure comparability, the screening and subsequent assessment of 
response should be performed using identical techniques. The same individual should assess 
images for any 1 subject for the duration of the study if possible. For subjects with known 
brain metastases at study entry, it is recommended that repeat imaging also include the brain 


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and the same methods used to detect brain lesions at baseline are to be used to follow the 
lesions throughout the study.  
Confirmation scans for CR or PR should be done at the next scheduled assessment. If a subject 
discontinues study drug prior to disease progression, the subject should continue to undergo 
local imaging assessment every 56 days (± 7 days) until PD is documented per investigator, the 
subject misses 2 or more consecutive scheduled tumor assessments, or the subject starts 
another anticancer treatment, whichever occurs earlier, in order to assess PFS#1.
The site of disease progression including target, non-target and/or new lesions should be 
documented in the eCRF. Additional imaging may be performed at any time to confirm 
suspected progression of disease.
5.3.1
Evaluation of Target Lesions
5.3.1.1 Complete Response (CR)
CR is defined as disappearance of all target and nontarget lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from 
baseline measurement.  
5.3.1.2 Partial Response (PR)
PR is defined as at least a 30% decrease in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum 
of diameters.  
5.3.1.3 Stable Disease (SD)
SD is defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify 
for progressive disease taking as reference the smallest sum of diameters while on study 
drug.  
5.3.1.4 Progressive Disease (PD)
PD is defined as at least a 20% increase in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of the target lesions taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. The appearance of 1 or more new lesions is also considered progression.
5.3.2
Evaluation of Nontarget Lesions
To achieve unequivocal progression on the basis of nontarget lesions, there must be an 
overall level of substantial worsening in nontarget disease such that, even in presence of SD 
or PR of target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of 1 or more nontarget lesions is 
usually not sufficient to qualify for unequivocal progression. 


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5.3.2.1 Complete Response (CR)
For CR of nontarget lesions, subjects must have disappearance of all nontarget lesions and all 
lymph nodes must be nonpathological in size (< 10 mm short axis).
5.3.2.2 NonCR/NonPD
NonCR/NonPD of nontarget lesions is defined as persistence of 1 or more nontarget lesions.
5.3.2.3 Progressive Disease (PD)
PD of nontarget lesions is defined as unequivocal progression of existing nontarget lesions or 
the appearance of 1 or more new lesions.
5.3.3
Evaluation of Time Point Response
The overall response status at each time point for subjects with measurable disease at 
baseline will be reported according to Table 1 in [Appendix 12.9].
5.3.4
Disease Control Rate (DCR)
The disease control rate is defined as the proportion of subjects whose best overall response 
is rated as CR, PR or SD among all analyzed subjects.
5.3.5
Progression-free Survival (PFS)
PFS is defined as the time from randomization to death from any cause or radiographic 
disease progression assessed according to RECIST V1.1, whichever occurs first.
5.4
Safety Assessment
5.4.1
Vital Signs
Vital signs, including systolic and diastolic blood pressures (mmHg), radial pulse rate 
(beats/minute) and temperature will be obtained according to the Schedule of Assessments
and recorded. All vital sign measures will be obtained with the subject in the sitting or supine 
position.
If clinically significant vital sign changes from baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance will be defined 
as a variation in vital signs, which has medical relevance as deemed by the investigator that 
could result in an alteration in medical care. The investigator will continue to monitor the 
subject until the parameter returns to Grade ≤ 1, or to the baseline (pretreatment) value, or until 
the investigator determines that follow up is no longer medically necessary.
5.4.2
Adverse Events
Adverse event collection will begin from time of informed consent and continue through the 
30-day follow-up visit, regardless of initiation of a new anticancer therapy or transfer to 
hospice. Serious adverse events considered related to the study drug should continue to be 
reported as long as the subject is being followed after study drug discontinuation and has not 
started a new anticancer treatment.  Adverse events will be documented at each clinic visit, 


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but can be collected at any time. Any AE that meets the definition of an SAE will also be 
reported on a separate form to the sponsor. 
See [Section 5.5] for information regarding AE collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin 
See [Appendix 12.2] for detailed information on liver abnormalities, monitoring and 
assessment, if the AE for a subject enrolled in a study and receiving study drug is accompanied 
by increases in liver function testing (LFT, e.g., AST, ALT, total bilirubin, etc.) or is suspected 
to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) 
abnormalities should be carefully monitored.  
5.4.3
Laboratory Assessments
A table of the laboratory tests that will be performed during the conduct of the study is found 
in [Appendix 12.11].  Laboratory tests will be performed predose according to the Schedule 
of Assessments and sent to a central laboratory for analysis. Additional assessments may be 
done centrally or locally to monitor adverse events or as required by dose modification 
requirements.
Additional laboratory tests should be performed according to institutional standard of care.  
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator or delegated Subinvestigator who is a qualified physician.  
5.4.4
Physical Examination 
Standard, full physical examinations will be performed to assess general appearance, skin, 
eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status, mental status, and lymphatic systems. Physical examinations will be 
conducted at visits as outlined in the Schedule of Assessments.  Each physical examination 
will include the observation and review of all body systems, and weight; height is only 
required at Screening.  If clinically significant worsening of findings from baseline is noted at 
any study visit, the changes will be documented as AEs on the AE eCRF. Clinical 
significance is defined as any variation in physical findings, which has medical relevance that 
could result in an alteration in medical care. The investigator will continue to monitor the 
subject until the parameter returns to Grade ≤ 1, or to the baseline condition, or until the 
investigator determines that follow-up is no longer medically necessary.
5.4.5
Electrocardiogram (ECG)
Single 12-lead ECGs will be conducted at visits as outlined in the Schedule of Assessments
and assessed locally. Whenever another study procedure time point coincides with an ECG 
time point, study procedures should be performed in the following sequence: ECG first, 
followed by vital signs, followed by any type of blood collection (safety labs or 
pharmacokinetics) last.  


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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the eCRF accordingly.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets 1 of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
The development of a new cancer should be regarded as an AE and will generally meet at 
least 1 of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study drug and have been identified after the subject’s inclusion in this 
study.  It does not include new metastases of the original cancer.
5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:
●
Results in death
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events


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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, should also 
usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
Disease progression can be considered as the worsening of a subject’s condition attributable 
to NSCLC.  It may be an increase in the severity of the disease under study and/or increases 
in the symptoms of the disease. The development of new, or progression of existing 
metastases to the primary cancer under study should be considered as disease progression and 
not an AE.  Events which are unequivocally due to disease progression should not be 
reported as an AE during the study.
Progression of NSCLC, including signs and symptoms of progression, should not be reported 
as an SAE unless it results in death within 30 days of the last dose of study drug. For 
progression-related death reported as an SAE as required, there should be available 
immediate cause of death reported as the event term.  “Death due to disease progression”
should be recorded as the adverse event term only when the cause of death cannot be 
otherwise determined.
Safety events of interest on the medicinal products administered to the subject as part of the
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the sponsor medicinal product (e.g., name confusion)
All of the events of interest noted above should be recorded on the eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and the SAE worksheet. 
The sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "AEs 
whose relationship to the study drugs could not be ruled out".


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Causal relationship to 
the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal  
relationship to drug administration which makes a causal relationship 
improbable, and/or in  which other drugs, chemicals or underlying disease 
provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals.  Information 
on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or  other drugs or chemicals and which follows a 
clinically reasonable response on re administration (rechallenge) or 
withdrawal (de-challenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) guidelines 
(Version 4.03).  The items that are not stipulated in the NCI-CTCAE Version 4.03 will be 
assessed according to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of an SAE, the investigator must contact the sponsor/delegated CRO by telephone 
or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the sponsor/delegated CRO by fax or email 
immediately (within 24 hours of awareness). If the faxing of an SAE Worksheet is not 
possible or is not possible within 24 hours, the local drug safety contact should be informed 
by phone.
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's Medical Monitor/Expert or his/her designee (see Section II). 


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Please fax or email the SAE worksheet for Japan (JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO) to:
or
 – Japan
Please fax or email the SAE worksheet for ROW to:
Astellas Pharma Global Development, Inc.
 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.
Full details of the SAE should be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
ISN/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The sponsor or sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies (i.e., FDA) as necessary, and will inform the investigators 
of such regulatory reports.  Investigators must submit safety reports as required by their 
IRB/IEC within timelines set by regional regulations (i.e., EU, eCTD, FDA).  Documentation 
of the submission to and receipt by the IRB/IEC of expedited safety reports should be 
retained by the site.
The sponsor/delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements of 
the IRB/IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor.
You may contact the sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare or rights of the subject.


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5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the investigator must immediately report the information to the sponsor. 
Please refer to [Appendix 12.2] for detailed instructions on drug-induced liver injury (DILI).
5.5.7
Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure.  SAEs classified as “common” are provided in [Appendix 12.3]. The list 
does NOT change reporting obligations or prevent the need to report an AE meeting the 
definition of an SAE as detailed above.  The purpose of this list is to provide an alert that some 
events reported as SAEs may not require expedited reporting to the regulatory authorities based 
on the classification of “common SAEs” as specified in [Appendix 12.3]. The sponsor will 
monitor these events throughout the course of the study for any change in frequency. Any 
changes to this list will be communicated to the participating investigational sites.  
Investigators must report individual occurrences of these events as stated in [Section 5.5.5]. 
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 90 days from the discontinuation of dosing, the investigator should report 
the information to the sponsor/delegated CRO as if it is an SAE. The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated 
conception date, pregnancy result and neonatal data etc., should be included in this 
information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the reporting procedure 
for SAEs.  Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth


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●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator.  The investigator will report the pregnancy to 
the sponsor/delegated CRO as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected ASP8273 overdose, the subject should receive supportive care and
monitoring. The Medical Monitor should be contacted as applicable.
In the event of suspected erlotinib or gefitinib overdose, refer to the approved Package Insert, 
SPC or local product information supplied by the manufacturer for each agent. 
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
The following 2 paragraphs are applicable to investigational sites in Japan:
1.
When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Enforcement Regulations of the 
Pharmaceutical Affairs Law, in compliance with Article 80-2 Paragraph 6 of the 
Pharmaceutical Affairs Law, the sponsor should inform all the investigators involved in 
the clinical study, the head of the study site, and the regulatory authorities of such 
information. The head of the study site who receives such information will decide 
whether the clinical study should be continued after hearing the opinions of the IRB.  
The investigator will supply the new information to the subjects, in compliance with 
[Section 8.2.3.2].
2.
In addition to the above item (1), when the head of the study site receives the revisions of 
the Investigator’s Brochure, protocol, or written information, information on the matters 
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly, or documents to be examined by the IRB should 
be sent to the IRB.
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-threatening 
Risks to Subjects (Unique to Japan)
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the investigator should take the following actions. 
1.
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice, and immediately send the document stating the deviation or amendment and the 
reasons to the sponsor and the head of the study site.  Keep a copy of the notice.


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2.
Consult with the sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the sponsor.
5.6
Test Drug Concentration
5.6.1
Pharmacokinetics
Blood samples will be collected to analyze plasma concentrations of unchanged ASP8273 and 
its metabolite(s) (if applicable) in subjects randomized to the ASP8273 arm as outlined in the 
Schedule of Assessments. For each ASP8273 sample, 2 mL of blood will be collected in a 
draw tube designated for research use only and processed. Blood sampling, processing, storage 
and shipment instructions will be provided in the Lab Manual. Samples will be shipped to and 
analyzed by a sponsor-designated analytical laboratory. Please refer to the Lab Manual for 
more detailed information.
5.7
Other Measurements, Assessments or Methods
5.7.1
Quality of Life and Patient Reported Outcomes
Subjects will be asked to complete the QoL and PRO questionnaires electronically at baseline 
and at day 1 of each cycle where a visit takes place. The questionnaires should be 
administered prior to the start of any assessments and before the disease status is discussed 
with the patient. The EQ-5D-5L only will also be administered at each of the posttreatment or 
long-term follow-up survival contacts for 6 months after treatment discontinuation.
5.7.1.1 FACT-EGFRI-18
The FACT-EGFR-18 is a PRO instrument specifically designed to assess the effect of EGFR 
inhibitors on quality of life. It consists of 18 items in 3 QoL domains: symptoms, functioning 
and emotions.
5.7.1.2 EORTC-QLQ-LC13
The EORTC-QLQ-LC13 module items evaluate lung cancer-specific symptoms such as 
cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or 
feet, hair loss and pain.
5.7.1.3 EORTC-QLQ-C30
The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional 
domain scales: physical, role, emotional, social and cognitive. 
5.7.1.4 EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome,
consisting of 6 items that cover 5 main domains (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a general visual analog scale for health status.


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5.7.2
Biomarkers
Plasma and whole blood samples will be collected as specified in the schedule of assessments 
for exploratory analysis of biomarkers and EGFR mutation status.  Formalin fixed paraffin 
embedded (FFPE) specimen, either from an archival specimen or from a recent biopsy, will 
be collected from all subjects. Eligibility may be determined by a previously documented 
EGFR mutation test result (L858R or exon 19 del). However, there should be sufficient 
tumor tissue from the specimen used to generate the EGFR test result to send to the central 
lab for confirmatory testing (10 unstained slides or FFPE block preferred, 7 slides 
minimum). If slides are submitted, the slides should be freshly cut from the FFPE block 
within 18 days of sending to the central lab. If a subject does not have a previously 
documented EGFR mutation test result, then a fresh formalin fixed paraffin embedded 
specimen (surgical resection, core needle biopsy or fine needle aspiration) must be obtained 
and set to the central lab for eligibility testing. Tissue slides may be retained for analysis at 
the central laboratory for up to 15 years.
A plasma sample for EGFR mutation detection will also be collected at baseline and at end of 
treatment and submitted to the central laboratory. For subjects who signed a separate ICF, an 
optional post-progression tumor tissue for exploratory analysis of biomarkers (e.g., EGFR 
mutation [T790M, C797S], c-Met mutation/amplification and AXL over expression) which 
are potentially related to EGFR-TKI drug response or resistance, will be collected following 
locally or centrally confirmed disease progression and prior to commencement of subsequent 
anticancer therapy.  
Plasma and tissue sampling, processing, storage and shipment instructions will be provided in 
the lab manual. Samples will be shipped to and analyzed by a sponsor-designated analytical 
laboratory. Please refer to the Lab Manual for more detailed instructions.
5.7.3
Sample for PGx Substudy
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety issues. After randomization (see 
Schedule of Assessments), a 4-mL sample of whole blood for possible retrospective PGx 
analysis will be collected and processed. Blood sampling, processing, storage and shipment 
instructions will be provided in the Lab Manual. Samples will be shipped to and analyzed by 
a sponsor-designated analytical laboratory.  Please refer to the Lab Manual for more detailed 
information.
See [Appendix 12.4] for further details on the banking procedures.
5.8
Total Amount of Blood
The total amount of blood collected for study assessments for each subject will vary 
depending on how long they stay on treatment.  
At any time during the study, if any laboratory abnormalities are found for a subject or for 
disease assessment, additional blood may be drawn for monitoring.


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Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment, hematology, chemistry, and coagulation at specific study 
defined time points, pharmacokinetics and bioanalytical sampling.
The maximum amount of blood collected per cycle is approximately 28.2 mL in cycle 1.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
The subject will be discontinued from the treatment period if any of the following occur:
●
Subject develops radiological progressive disease (i.e., PFS#1) per RECIST v1.1 based 
on central confirmation of investigator assessment
o
If there is radiographic evidence of PD by investigator, however the investigator 
believes the subject is continuing to derive clinical benefit (asymptomatic and/or 
without worsening of performance status or overall health) from study drug, and 
an increase in tumor burden is not likely to affect vital organ function, the subject 
may remain on study drug until the next scheduled radiographic assessment which 
should occur after 56 days (± 7 days). 
o
If the next radiographic assessment indicates PD per RECIST 1.1 which is 
confirmed by the central reviewer, then the subject must be discontinued from 
study drug. 
o
In the rare event where PD suspected on initial assessment is not confirmed on 
subsequent scan by the investigator or central reviewer, the subject may continue 
in the study. 
o
The investigator should make every effort to immediately submit radiographic 
assessments for central review when PD is either suspected or confirmed or 
uncertainty exists.
o
In case of PD determination by the investigator, however not confirmed by the 
central reviewer, and subject is progressing clinically and requires new 
anti-cancer treatment immediately, the subject should be discontinued.
●
Subject is required to receive local or systemic anti-cancer treatment based on 
investigator’s clinical opinion.
●
Subject develops unacceptable toxicity
●
Female subject becomes pregnant


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●
Investigator decides it is in the subject’s best interest to discontinue including clinical 
progression
●
Requirement for significant surgical procedure; however, if surgical procedure is for the
resection of the primary or metastatic lesion, the subject may be eligible to continue on 
study treatment after discussion with the Medical Monitor
●
Significant deviation from the protocol or eligibility criteria
●
Subject declines further treatment
●
Subject is noncompliant with the protocol based on the investigator or Medical Monitor 
assessment
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Death
The subject may be discontinued from the study if there is an interruption of treatment for 
> 14 consecutive days despite optimal treatment of side effects.  A discussion with the 
Medical Monitor should occur to confirm if the subject should continue on study treatment.
Subjects who discontinue study drug and enter the posttreatment follow up period prior to 
reaching PFS#1 will be discontinued from the posttreatment period if any of the following 
occur:
●
Subject develops radiological progressive disease (i.e., PFS#1) based on investigator 
assessment
●
Subject initiates a new systemic anticancer treatment
●
Subject misses 2 consecutive scheduled tumor assessments
The subject will be discontinued from the long-term follow-up period (for PFS#2) if any of 
the following occur:
●
Subject initiates a new systemic anticancer treatment (3rd line)
●
Subject exhibits evidence of PD from 2nd line therapy based on investigator assessment
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Death
●
Sponsor ends long-term follow-up collection period
The subject will be discontinued from the survival follow-up period if any of the following 
occur:
●
Subject declines further study participation (i.e., withdraws consent)
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Death
●
Sponsor ends survival follow-up period


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6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.
6.3
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD.  A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced.  The SAP will be finalized 
before enrollment of the first subject.  Any changes from the analyses planned in SAP will be 
justified in the clinical study report (CSR).
Prior to Database Lock, a Final Review of Data and TLFs Meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented.  A meeting to determine analysis set classifications may also be held prior to 
database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
Approximately 600 subjects will be randomized in a 1:1 ratio to 2 treatment arms: Arm A 
(ASP8273) and Arm B (erlotinib or gefitinib). Randomization will be stratified by ECOG PS 
(0, 1 or 2), EGFR mutation type (exon 19 deletion or mutation in exon 21 [L858R]), TKI 
chosen (erlotinib versus gefitinib) and race (Asian versus nonAsian). Assuming HR=0.667 
(median PFS in Arm A and Arm B are 15.6 months and 10.4 months, respectively), a total of 
420 PFS events will provide approximately 98.7% power to detect a statistically significant 
difference at type I error rate of 1-sided 0.025.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 


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7.2.1
Full Analysis Set (FAS)
The full analysis set will consist of all subjects who are randomized.  This will be the primary 
analysis set for efficacy analyses.
7.2.2
Per Protocol Set (PPS)
The per protocol set will consist of the subset of the FAS who do not meet criteria for PPS 
exclusion.  These criteria are to capture relevant nonadherence to the protocol and will be 
defined in the SAP.  In addition, subjects in the PPS are required to have both baseline 
imaging and at least 1 postbaseline imaging scan. The PPS will be a secondary analysis set 
for efficacy analyses.  Select demographic and baseline characteristics may also be 
summarized for the PPS.
7.2.3
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used.  The 
SAF consists of all subjects who take at least 1 dose of study medication, and will be used for 
safety analyses.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which at least one plasma concentration data is available for whom the time of dosing on the 
previous day of sampling is known. Additional subjects may be excluded from the PKAS at 
the discretion of the pharmacokineticist. Any formal definitions for exclusion of subjects or 
time-points from the PKAS will be documented in the Classification Specifications and 
determined in the Classification Meeting. 
7.2.5
Pharmacodynamics Analysis Set (PDAS) 
The biomarker pharmacodynamics analysis set (PDAS) will include the subjects from the 
SAF population for whom sufficient pharmacodynamic measurements were collected. The 
PDAS will be used for all analyses of pharmacodynamics data.
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group for 
the SAF.  Descriptive statistics will include number of subjects, mean, standard deviation, 
minimum, median and maximum for continuous endpoints, and frequency and percentage for 
categorical endpoints. 
7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS and PPS.  The interpretation of results from 
statistical tests will be based on the FAS.  The PPS will be used to assess the robustness of 
the results from the statistical tests based on the FAS.  All randomized subjects will be 
analyzed according to the treatment to which they are randomized.


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7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The primary endpoint is PFS assessed by the blinded IRR.  For each subject, PFS is defined as 
the time from the date of randomization until the date of radiological disease progression
(i.e., PFS#1) assessed by IRR, or until death due to any cause. If a subject has neither 
progressed nor died, the subject will be censored at the date of last radiological assessment.  
Subjects who receive any further anticancer therapy for the disease before radiological 
progression will be censored at the date of the last radiological assessment before the 
anticancer therapy started. If progression or death occurs after missing 2 scheduled radiological 
assessments, the subject will be censored at the date of last radiological assessment or at the 
date of randomization if no postbaseline radiological assessment is available.
The primary analysis will be performed when approximately 420 PFS#1 events have been 
observed.
The distribution of PFS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using log-rank test stratified by ECOG 
PS (0 and 1 combined versus 2), EGFR mutation type, and TKI chosen (erlotinib versus 
gefitinib).  In addition, stratified Cox proportional hazard model will be used to estimate the 
hazard ratio and the corresponding 95% confidence interval.
The primary analysis will be performed using the FAS.
7.4.1.2 Secondary Analysis
The same analysis of the primary endpoint as described in [Section 7.4.1.1] will be conducted 
using the PPS.  
7.4.1.3 Subgroup Analysis
The analysis described in [Section 7.4.1.1] will be conducted in the subgroups using the FAS.
Forest plot will be presented to illustrate the strength of treatment effects across subgroups 
defined by baseline factors.
7.4.2
Analysis of Secondary Endpoints 
7.4.2.1 Overall survival
OS is defined as the time from the date of randomization until the documented date of death 
from any cause.  All events of death will be included, regardless of whether the event 
occurred while the subject is still taking study drug or after the subject discontinue study 
drug. Subjects who are still alive at the time of analysis will be censored at the last day 
known to be alive.  
The distribution of OS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test stratified by 
ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 deletion or mutations 
in exon 21 [L858R]) and TKI chosen (erlotinib versus gefitinib). In addition, stratified Cox 


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proportional hazard model will be used to estimate the hazard ratio and the corresponding 
95% confidence interval.
7.4.2.2 Best overall response rate (ORR)
Best overall response is determined once all tumor response data for the subject is available.  
Subjects will be classified by best response on study as outlined in RECIST V1.1 criteria.  
For best overall response of SD, SD must be documented as present at least once after study 
entry and at least 7 weeks after first dose.
The ORR is defined as the proportion of subjects with a complete or partial objective 
response based on the RECIST V1.1. 
The ORR (confirmed) is defined as the proportion of subjects with a confirmed complete or 
partial objective response based on the RECIST V1.1 in Table 3 of [Appendix 12.9]. 
The comparison of ORR between Arm A and Arm B will be performed using stratified CMH 
test.  In addition, ORR for each arm will be estimated and corresponding 95% confidence 
interval will be constructed.
The comparison of ORR (confirmed) between Arm A and Arm B will be performed using 
stratified CMH test. In addition, ORR for each arm will be estimated and corresponding 95% 
confidence interval will be constructed. This will be a sensitivity analysis.
Hochberg procedure will be used to control the overall error rate at 1-sided 0.025 level for 
the secondary efficacy endpoints (OS and ORR). Only when the primary endpoint 
significantly favors the ASP8273 arm will secondary endpoints be tested.
7.4.2.3 PFS by the Investigator
For each subject, PFS is defined as the time from the date of randomization until the date of 
radiological disease progression assessed by the investigator, or until death due to any cause.  
If a subject has neither progressed nor died, the subject will be censored at the date of last 
radiological assessment. Subjects who receive any further anticancer therapy for the disease 
before radiological progression will be censored at the date of the last radiological 
assessment before the anticancer therapy started.  If progression or death occurs after missing 
2 consecutive scheduled radiological assessments, the subject will be censored at the date of 
last radiological assessment or at the date of randomization if no postbaseline radiological 
assessment is available.
The distribution of PFS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using stratified log-rank test as 
specified in [Section 7.4.1.1].  In addition, stratified Cox proportional hazard model will be 
used to estimate the hazard ratio and the corresponding 95% confidence interval.
7.4.2.4 Disease Control Rate (DCR)
The DCR is defined as the proportion of subjects with a complete or partial objective 
response or a stable disease based on RECIST V1.1. 


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The comparison of DCR between Arm A and Arm B will be performed using CMH test 
stratified by ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 deletion 
or mutations in exon 21 [L858R]) and TKI chosen (erlotinib versus gefitinib). In addition, 
DCR for each arm will be estimated and corresponding 95% confidence interval will be 
constructed.
7.4.2.5 Duration of Response (DOR)
DOR is defined as the time from the date of the first response CR/PR (whichever is first 
recorded) as assessed by IRR to the date of radiographic progression or date of censoring. If a 
subject has not progressed, the subject will be censored at the date of last radiological 
assessment or at the date of first CR/PR if no post-baseline radiological assessment is 
available. 
The distribution of DOR will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test stratified by 
ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 deletion or mutations 
in exon 21 [L858R]) and TKI chosen (erlotinib versus gefitinib). In addition, stratified Cox 
proportional hazard model will be used to estimate the hazard ratio and the corresponding 
95% confidence interval.
7.4.2.6 QoL and PRO Parameters
Descriptive QoL and PRO analyses will be performed on the FAS. Completion rate for each 
questionnaire will be summarized. Additional analyses will be discussed in details in the 
statistical analysis plan.
7.4.3
Analysis of Exploratory Endpoints 
7.4.3.1 PFS on Next-Line Therapy (PFS#2)
PFS#2 is defined as the time from initiation of new systemic anti-cancer treatment (excluding 
local radiation, surgical removal of metastatic site or protocol defined Erlotinib or Geftinib or 
ASP8273 based on initial treatment allocation per subject) to investigator-determined 
progression, discontinuation of new treatment, start of a different treatment or death from any 
cause, whichever comes first. Otherwise, subjects will be censored.
Subjects who have not started new systemic anti-cancer treatment will be censored at Day 1. 
Subjects who are alive, started new systemic anti-cancer treatment and for whom a PFS#2 
event has not been observed should be censored at the last time known to be alive.
The distribution of PFS#2 will be estimated for each treatment arm using Kaplan-Meier
methodology and compared between Arm A and Arm B using stratified log-rank test as 
specified in [Section 7.4.1.1].  In addition, stratified Cox proportional hazard model will be 
used to estimate the hazard ratio and the corresponding 95% confidence interval.
7.4.3.2 Other Exploratory Analyses
Exploratory assessment of pharmacokinetic-pharmacodynamic relationships will be performed.


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7.5
Analysis of Safety
All treated subjects will be analyzed according to the treatment they received.
7.5.1
Adverse Events 
Adverse events will be coded using MedDRA.  The number and percentage of AEs, SAEs, 
AEs leading to discontinuation and AEs related to study drug will be summarized by system 
organ class, preferred term and treatment group. The number and percentage of AEs by 
severity will also be summarized. All AEs will be listed.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point.  Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated.  Laboratory data will be displayed in listings.
7.5.3
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.  Vital signs data will be displayed in listings.
7.5.4
Physical Examination
Physical examination will be listed by treatment group.
7.5.5
ECGs 
The 12-lead ECG results will be summarized by treatment group and time point.
7.5.6
Concomitant Medication
The frequency of concomitant medications (prescription, over-the-counter, and nutritional 
supplements) will be summarized by preferred term. Medications will be coded using the
WHO drug dictionary.  Medications will be counted by the number of subjects who took each 
medication.  To count the number of subjects who took a medication, a subject taking the 
same medication multiple times will only be counted once for that medication.  Medications 
will be presented in decreasing order of frequency based on the total number of subjects who 
took each medication.
7.5.7
ECOG Performance Status
Summary statistics (number and percent of subjects) for each category of the ECOG 
performance status at each assessment will be provided.  The change from baseline to final 
visit or early termination will also be summarized. Negative change scores indicate an 
improvement. Positive scores indicate a decline in performance.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation and geometric mean) will be provided for plasma concentrations of 


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ASP8273 and its metabolite(s) (if applicable) at each visit. Additional model-based analyses 
may be performed and reported separately.
7.7
Analysis of Biomarkers 
Exploratory analysis may be performed for plasma biomarkers.  Details will be provided in 
the SAP.
7.8
Protocol Deviations and Other Analyses  
Protocol deviations as defined in [Section 8.1.6] will be summarized for all subjects in the 
FAS by treatment group and site totals will also be provided.  A data listing will be provided 
by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing.  
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim futility analysis is planned to occur after 210 PFS events are observed, which is 
expected to occur approximately 22 months after the first subject is randomized. If the 
observed HR is less than 1.1, recruitment into the study will continue as planned until 
600 subjects are recruited.  If the observed HR at the interim is larger than 1.1, recruitment 
into the study may be stopped at the interim analysis. Further review of the efficacy data, 
including secondary endpoints, will be performed by the sponsor to determine whether other 
evidence of clinical benefit justifies reopening enrollment. If the data do not justify reopening 
enrollment, enrollment may remain closed, and a decision will be made by the sponsor 
regarding termination of the study.  If the futility analysis takes place after enrollment is 
completed and the HR is greater than 1.1, subjects who in the opinion of the investigator and 
the sponsor’s Medical Monitor are continuing to derive benefit may continue to receive study 
drug as randomized.  As the interim analysis is for futility only, type I error at final analysis 
will not be affected.
The interim analysis will be conducted by the IDMC.  In addition safety data reviews during 
the trial will be conducted by the IDMC on a periodic basis. For example, the IDMC will 
review safety data after the first 50 patients have been randomized and on study drug for 
approximately 3 months.  The full procedures for IDMC safety review will be described in a 
separate IDMC charter.


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7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done.  Exceptions are the start 
and stop dates of AEs and concomitant medication.  The imputed dates will be used to 
allocate the concomitant medication and AEs to a treatment group, in addition to determining 
whether an AE is/is not treatment-emergent.  Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown.
Subjects with missing overall response assessment will be regarded as nonresponders in ORR 
analysis.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system.  In the interest of collecting data in the most efficient manner, the investigator
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within 5 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents.  
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at a central laboratory.  Laboratory data will be transferred 
electronically to the sponsor or designee at predefined intervals during the study.  The 
laboratory will provide the sponsor or designee with a complete and clean copy of the data. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
ePRO
Subject diaries and questionnaires will be completed by the subject or site (as applicable for 
phone collection of QoL) on an electronic device.  The information completed by the subject 
on the electronic device will be automatically uploaded into a central website.  The investigator
or site designee should review the diaries and questionnaire data on the website for correct 
completion while the subject is at the site.  The diary and questionnaire data will be transferred 
electronically to the sponsor or designee at predefined intervals during the study.  The vendor 
will provide sponsor or designee with a complete and clean copy of the data.


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8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The following information should be included in the source medical records:
●
Demographic data (date of birth, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated ICFs 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
Adverse events and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Smoking history (in pack-years)
●
Laboratory printouts
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number 
8.1.3
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/subinvestigator are accurate and complete and that they are verifiable with 
study-related records such as source documents.  The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring.  They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 
(refer to [Section 8.1.2]) when they are requested by the sponsor monitors and auditors, the 
IRB/IEC, or regulatory authorities.  The confidentiality of the subject's identities shall be well 
protected consistent with local and national regulations when the source documents are 
subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by Data Science of the sponsor in accordance with the 
SOPs for data management. All study-specific processes and definitions will be documented 
by Data Management. eCRF completion will be described in the eCRF instructions. Coding 


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of medical terms and medications will be performed using MedDRA and WHO Drug 
Dictionary respectively.
8.1.6
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to the sponsor are defined 
as any subject who: 
●
Entered into the study even though they did not satisfy entry criteria
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose
●
Received excluded concomitant treatment
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the sponsor is notified.  The sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File (TMF).  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as applicable. 
8.1.7
End of Trial in All Participating Countries
The study completion is defined as the conclusion of data collection for the defined study 
endpoints. Subjects continuing to derive clinical benefit are allowed to continue to receive 
treatment in the study after study completion. The end of study in all participating countries 
is therefore defined as the Last Subject’s Last Visit, or last contact. The study may be closed 
within a participating country per local regulations after the study has completed if all 
subjects enrolled in the country are no longer receiving study treatment.


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8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA)
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) as well as any other necessary documents be 
reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, ICF
and subject information and/or advertising, as relevant, will be obtained prior to the 
authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required.  During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to the 
sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year.  The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies, or for APEB/APEL-sponsored studies 
within 1 year after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the ICF will be 
reviewed and signed and dated by the subject or his/her guardian or  legal representative, the 
person who administered the informed consent and any other signatories according to local 
requirements.  A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record.  An entry must also be made in the subject’s dated 


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source documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction).  The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC.  The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study.  The investigator
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally.  The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF.  A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record.  An entry must be made in the subject’s records documenting the 
reconsent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited.  Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The sponsor affirms the subject's right to protection against invasion of privacy.  Only a 
subject identification number and/or initials will identify subject data retrieved by the 
sponsor.  However, the sponsor requires the investigator to permit the sponsor, sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e., HIPAA). 


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8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor.  Details should be disclosed only to the persons involved in the 
approval or conduct of the study.  The investigator may use this information for the purpose 
of the study only.  It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies.  In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs and Investigator's File) and relevant correspondence.  These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, 2 years 
after approval of the NDA or discontinuation of the IND).  The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued.  The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records.  The sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.  All data will be entered in the eCRFs for each 
subject. 
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or nonsubstantial amendments.  
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the sponsor, the investigator, the regulatory authority and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the sponsor.


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8.3.4
Insurance of Subjects and Others 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File.
If a subject suffers any study-related injury, the sponsor will compensate appropriately 
according to the severity and duration of the damage.  However, if it was caused intentionally 
or was due to gross negligence by the study site, the sponsor will consult with the study site 
about handling the injury, based on the agreed study contract.  Compensation for the study-
related injury is provided by the following procedures:
1.
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures. The sponsor should be 
notified of the injury. 
2.
When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the sponsor. Both parties should work together towards
compensation settlement. 
3.
The sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract. 
4.
The sponsor shall make an arranging for insurance and take measures necessary to ensure 
the compensation or indemnification mentioned above.
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock.
9
QUALITY ASSURANCE
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s).
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities.  The audit may include on-site review of regulatory 


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documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors. 
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s)
An independent Data Monitoring Committee will be responsible for evaluating safety data on 
a periodic basis during the study and to review results of the planned futility analysis. The 
IDMC will minimally consist of medically qualified individuals and a statistician. A separate 
IDMC charter will specify the governance and conduct of the IDMC.
10.2
Other Study Organization
Not applicable.


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11
REFERENCES 
Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, et al. Epidermal growth 
factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular 
analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005;23:8081-92.
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
Esposito L, Conti D, Ailavajhala R, Khalil N, Giordano A. Lung cancer: are we up to the challenge? 
Curr Genomics. 2010;11:513-8.
Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and 
mortality in Europe in 2006. Ann Oncol. 2007;18:581-92.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Eng J Med. 2008;359:1367-80.
Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and 
resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786-92.
Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 
2008;21(Suppl 2):S16-S22.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or 
chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 
2010;362:2380-8.
Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 
2000;19:6550-65.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, et al. Updated overall survival 
results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin 
plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer 
harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol. 
2012;30(suppl;abstr 7521).
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin 
plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the 
epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. 
Lancet Oncol. 2010;11:121-8.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin–
paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361: 947-57.
Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase 
inhibitor-resistant disease. 2013;31:1070-80.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung 
adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR 
kinase domain. PLoS Med. 2005;2:e73.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard 
chemotherapy as first-line treatment for European patients with advanced EGFR mutation-
positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 
trial. Lancet Oncol. 2012;13:239-46. 


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Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung 
cancer. Nat. Rev. Cancer. 2007;7:169-81.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological 
features associated with epidermal growth factor receptor gene mutations in lung cancers. J 
Natl Cancer Inst. 2005;97:339-46.
Wells A. EGF receptor. Int J Biochem Cell Biol. 1999;31: 637-43.
Zhou C, Wu YL, Liu XQ, Wang C, Chen G, Feng J, et al. Overall survival (OS) results from 
OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine 
(GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-
small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl;abstr 7520).
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line 
treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer 
(OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet 
Oncol. 2011;12:735-42.
Company Reports:
Investigator’s Brochure. ASP8273 mesilate for the treatment of non-small cell lung cancer. Edition 3. 
Astellas Pharma Global Development, Inc. January 21, 2015.
Package Insert, Erlotinib, Genentech/Astellas, 2012 (available at https://www.astellas.us/docs/tarceva.pdf)
Package Insert, Gefitinib, Astrazeneca, 2014 (available at http://www.iressa.com/product-
information.html)
Data on file for ASP8273


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 or erlotinib/gefitinib, and will be strictly prohibited:
Arm A (ASP8273)

Chemotherapy, radiotherapy, 
immunotherapy or other medications 
intended for antitumor activity.

Investigational products or therapy other 
than ASP8273.

Potent inhibitors or inducers  of CYP3A4 

CYP3A4 and/or P-gp substrates with a 
narrow therapeutic index
Arm B (Erlotinib/Gefitinib)

Chemotherapy, radiotherapy, immunotherapy 
or other medications intended for antitumor 
activity other than erlotinib/gefitinib.

Investigational products or therapy.

Potent inhibitors or inducers of CYP3A4 

Proton pump inhibitors or drugs that cause 
significant elevation in gastric pH
Examples for excluded inhibitors, inducers and substrates for enzymes and transporters are 
provided below. This list should NOT be considered all inclusive. Investigators will consult 
individual drug labels to determine liability of the drugs. 
Excluded CYP Inhibitors/Inducers
CYP3A4
Inhibitors
Potent: boceprevir, clarithromycin, conivaptan, grapefruit juice*, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole
*The effect of grapefruit juice varies widely among brands and is 
concentration-, dose- and preparation dependent.
Inducers
Potent: avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort
Excluded Drugs with Narrow Therapeutic Index
CYP3A4 substrates 
Alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine
P-gp substrates
Cyclosporine, digoxin, sirolimus
Additional information for inhibitors/inducers/substrates of enzymes/transporters can be 
found in FDA’s guidance (Guidance for Industry Drug Interaction Studies - Study Design, 
Data analysis, and Implications for Dosing and Labeling)1 and from the Division of Clinical 
Pharmacology of Indiana University2.
1.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM292362.pdf
2.
http://medicine.iupui.edu/clinpharm/ddis/main-table/


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or total bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at 
least ALT, AST, ALP, and TBL). Testing should be repeated within 48 to 72 hours of 
notification of the test results. Alerts will be generated by the central lab regarding moderate 
and severe liver abnormality to inform the investigator, study monitor and study team.  
Subjects should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN (in patients without liver 
metastases), > 5 x ULN (in patients with liver 
metastases)
or
> 2 x ULN
Severe*
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases)
●
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests.  The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) that has been developed globally and can be activated for any 
study.  Subjects with confirmed abnormal liver function testing should be followed as 
described below. 
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology may be considered an important medical event and may be reported as an SAE.  The 


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sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases should be recorded as ‘AEs’ on the AE page of eCRF.  Illnesses 
and conditions such as hypotensive events, and decompensated cardiac disease that may 
lead to secondary liver abnormalities should be noted.  Nonalcoholic steatohepatitis 
(NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients and may be 
associated with fluctuating aminotransferase levels.  The investigator should ensure that 
the medical history form captures any illness that predates study enrollment that may be 
relevant in assessing hepatic function.    
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets.  Medications, including dose, should be entered on the concomitant 
medication page of the eCRF.  Information on alcohol, other substance use and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
o
acute viral hepatitis (A, B, C, D, E or other infectious agents). 
o
ultrasound or other imaging to assess biliary tract disease
o
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study.  The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant).” The 2 “requirements” for Hy’s Law are: 1) evidence that a drug 
can cause hepatocellular-type injury, generally shown by an increase in transaminase 
elevations higher than 3 times the upper limit of normal (“2 x ULN elevations are too 
common in treated and untreated patients to be discriminating”) and 2) cases of increased 
bilirubin (at least 2 x ULN) with concurrent transaminase elevations at least 3 x ULN and no 
evidence of intra- or extra-hepatic bilirubin obstruction (elevated alkaline phosphatase) or 
Gilbert’s syndrome [Temple 2006].
References
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.
Temple R. Hy's law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.


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12.3
Common Serious Adverse Events
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied.  The list does NOT change reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2].  The 
purpose of this list is to provide an alert that some events reported as SAEs may not require 
expedited reporting to the regulatory authorities based on the classification of “common 
SAEs”.  You are required to follow the requirements detailed in [Section 5.5.5].
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA.  
AEs most likely related to NSCLC (Terms to be included in this list): 
●
Shortness of breath (dyspnea)
●
Cough
●
Chronic Cough
●
Respiratory infections
●
Chronic Respiratory Infections
●
Cachexia (weight loss not considered cachexia by investigators, not included)
●
Bone pain (if stage IV with distal metastases) 
●
Fever (if stage IV or symptom of infection)
●
Paraneoplastic syndromes.  Paraneoplastic syndromes can include but are not limited to 
myasthenic syndrome (AB to muscles); hypercalcemia; SIADH, Horner’s syndrome if a 
pancoast tumor and muscle weakness of the hands resulting from invasion of the brachial 
plexus.
●
Loss of appetite


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12.4
Retrospective PGx Substudy 
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject.  Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies 
(GWAS), the relationship between gene profiles and a drug’s kinetics, efficacy or toxicity 
may be better understood.  As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory.  The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx
substudy.  As part of this substudy, subjects must provide separate written consent prior to 
providing any blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this substudy will provide one 4-mL tube of blood per 
Astellas’ instructions.  Each sample will be identified by the unique subject number (first 
code).  Samples will be shipped frozen to a designated banking CRO either directly from site 
or via a central laboratory as directed by Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet.  Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety.  Prior to initiating any analysis on the banked samples, the 
Astellas Research Ethic Committee (AREC) must approve the analysis plan. 
DISPOSAL OF PGx SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard lock.  If there is no requirement for analysis, the blood sample will be 
destroyed after the planned storage period.  The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed.  The results of any PGx analysis conducted on a sample prior to its withdrawal 
will be retained at Astellas indefinitely.


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INFORMATION DISCLOSURE TO THE SUBJECTS
The PGx substudy may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date.  Any information that is obtained 
from the PGx analysis will be the property of Astellas. 




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12.6
EORTC-QLQ-LC13
Patients sometimes report that they have the following symptoms or problems. Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week. Please answer by circling the number that best applies to you.


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12.7
EORTC-QLQ-30


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12.8
EQ-5D-5L


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12.9
RECIST V1.1


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Reproduced from:  Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation 
criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-247


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12.10 ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair
5
Dead
Reproduced from: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-55


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12.11 Laboratory Assessments
Laboratory tests will be performed predose according to the Schedule of Assessments and 
sent to a central laboratory for analysis.
Panel/Assessment
Parameters to be analyzed 
Hematology
Hematocrit (Hct)
Hemoglobin (Hgb)
Red Blood Cell Count (RBC)
White Blood Cell Count (WBC)
WBC differential
Platelets
Mean Corpuscular Volume (MCV)
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
Biochemistry (fasting)
Sodium (Na)
Magnesium (Mg)
Creatine Phosphokinase (CK)
Potassium (K)
Calcium (Ca)
Corrected Serum Calcium
Chloride (Cl)
Phosphate (P)
Creatinine (Cr)
Glucose (Gl)
Blood Urea Nitrogen (BUN)
Alkaline Phosphatase (ALP)
Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
Lactate Dehydrogenase (LDH)
Bilirubin Total (TBL) (total and direct)
Total Protein (TP)
Albumin (Alb)
Bicarbonate (HCO3)
Serum HCG for female subjects of childbearing potential
Serum osmolality
Urinalysis 
Protein
Glucose
pH
Occult Blood
Ketones
Bilirubin
Urobilinogen
Sodium
Potassium
Chloride 
Urine osmolality
Coagulation Profile
PT (sec)
APTT
INR


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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Substantial Changes
1.
Revise Study Secondary Objectives  
DESCRIPTION OF CHANGE:
Duration of Response (DOR) is added as a secondary endpoint and Quality of Life (QoL) is
moved from an exploratory to a secondary endpoint.  
RATIONALE:
DOR and QoL are both important clinical endpoints.  Adding these 2 endpoints as secondary 
endpoints will not affect the analysis of the primary and key secondary endpoints for the 
following reasons: (1) the Hochberg procedure is used to control the key secondary endpoints 
of overall survival (OS) and overall response rate (ORR) (2) only when the primary endpoint 
significantly favors the ASP8273 arm will the secondary endpoints be tested.
2.
Increase Planned Sample Size
DESCRIPTION OF CHANGE:
The sample size of this study is increased from 540 to 600 patients and the total number of 
study centers is increased from 200 to 240 centers.  Revisions are made accordingly to the 
number of events required for interim and final analysis.
RATIONALE:
Based on the mechanism of action of ASP8273 and available clinical data, it is likely that the 
separation of progression free survival (PFS) curves will occur late in Study 9287-CL-0302. 
As this study is the single pivotal study for registration, the sample size is increased to 
600 patients to make sure that the study has adequate power if late separation occurs.
3.
Clarify the Method of Comparator Selection
DESCRIPTION OF CHANGE:
Additional description is added to clarify that sites will choose one comparator to be used for 
all subjects at their site, rather than choosing for each individual subject during screening
RATIONALE:
In order to ensure consistency throughout the study and to limit potential bias in comparator 
choice.  Potential bias may occur if the comparator is chosen after review of a potential study 
participant’s clinical profile.  
4.
Update Imaging Requirements


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DESCRIPTION OF CHANGE:
Adding imaging of the brain as a requirement for all subjects at baseline.  
RATIONALE:
Non-small cell lung cancer (NSCLC) commonly metastasizes to the brain.  Based on this 
patient population and to ensure that progression is accurately determined post-baseline, 
brain imaging is to be done at baseline to document the presence or absence of metastatic 
lesions to the brain. 
5.
Update Contraception Requirements
DESCRIPTION OF CHANGE:
Revisions are made to the text for contraception requirements to more clearly define 
acceptable versus highly effective birth control methods.
RATIONALE:
As requested by several European Regulatory/Ethics committees, to be consistent with the 
EU Heads of Medicines Agency (HMA) Clinical Trial Facilitation Group (CTFG) guidelines.
6.
Clarify Study Eligibility Criteria
DESCRIPTION OF CHANGE:
Revisions are made to inclusion/exclusion criteria to provide additional clarity on epidermal 
growth factor receptor (EGFR) testing, measurable lesion requirements and previous 
treatment.
RATIONALE:
Clarifying language is added to further explain these eligibility requirements based on 
frequently received questions to date.
7.
Update Dose Modification Guidelines
DESCRIPTION OF CHANGE:
Dose modification guidelines are updated to include specific guidance for events of suspected 
or confirmed interstitial lung disease (ILD), ocular toxicities and hepatic impairment for all 
study drugs.  Explicit guidelines for gefitinib based on severity grade are added.  Clarification 
on interruption duration is added.  Guidance for ASP8273 dose modification is updated to 
allow re-escalation of the dose.
RATIONALE:
Updates to dose reduction/interruption guidelines are made consistent with the commitment 
in the response to FDA comments to include this in the upcoming amendment.  The 
instruction for ASP8273 de-escalation/re-escalation are revised based on experience to date 
in the early phase studies.  Guidance to minimize the drug interruption duration is added 
based on data on disease progression following drug interruption in the early phase studies.


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8.
Provide Additional Clarification for Criteria For Treatment After Progression
DESCRIPTION OF CHANGE:
Criteria are added that must be met to allow subjects to continue protocol-assigned treatment 
after documentation of radiological progressive disease.  More detailed guidance is added for 
determining progression at the next radiographic assessment.  
RATIONALE:
Updates are made consistent with current practice per NCCN guideline in alignment with 
current standard of care for treatment after progression, as well as per the commitment in the 
response to FDA comments to include this in the upcoming amendment. 
9.
Update Concomitant Medication Restrictions
DESCRIPTION OF CHANGE:
Revisions are made to the concomitant medication restrictions for ASP8273, erlotinib and 
gefitinib to provide more details around toxicity management of interstitial lung disease, 
ocular toxicity and hepatotoxicity.
RATIONALE:
Updates are made to ensure consistency with current package insert for the commercial 
comparator products.  In addition, fluconazole is a moderate CYP3A4 inhibitor according to 
the FDA guideline, and therefore should not be listed as strongly prohibited. The protocol 
text is being updated to be consistent with Appendix 12.1 which is correct.
Non-substantial Changes
1.
Update Sponsor contact information
DESCRIPTION OF CHANGE: 
Provide current key sponsor contact information and update serious adverse event (SAE) 
reporting details for Japan.
RATIONALE:
Update to reflect changes to the global medical lead and clinical research study team and 
addition of 
 contract research organization (CRO) support for SAE processing in 
Japan.
2.
Revision of Study Drug Storage Requirements 
DESCRIPTION OF CHANGE:
Storage requirements are updated for erlotinib and gefitinib.
RATIONALE:
To be consistent with commercial and study labeling for comparator study drugs.


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3.
Minor administrative-type corrections and clarifications
DESCRIPTION OF CHANGE:
Other minor corrections, e.g., typographical errors, formatting, clarifications, deletions. 
RATIONALE:
To ensure accuracy and clarity throughout protocol based on errors discovered and questions 
received on the protocol to date.
II. Amendment Summary of Changes: Substantial 
IV Synopsis, Study Objective, Endpoints for Evaluation and 2 Study Objective(s), 
Design, and Endpoints
2.1.2 Secondary Objectives, 2.1.3 Exploratory Objectives, 2.3.2 Secondary Endpoints and 
2.3.3 Exploratory Endpoints
WAS:
2.1.2 Secondary Objectives

Overall survival (OS)

Overall response rate (ORR) as assessed by IRR

PFS as assessed by the investigator

Disease control rate (DCR) as assessed by IRR

Safety of ASP8273
2.1.3 Exploratory Objectives

To evaluate potential biomarkers that may affect treatment outcome

Evaluation of the pharmacokinetics of ASP8273

To evaluate the impact of subsequent therapy on progression free survival on next-
line therapy (PFS#2)

To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) parameters as 
measured by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-QLQ-C30 and EQ-5D-
5L
2.3.2 Secondary Endpoints

OS

Best overall response rate (CR + PR) by IRR

PFS by the investigator

Disease control rate (CR+PR+SD) by IRR

Safety variables (e.g., AEs, laboratory tests, vital sign measurements, ECGs)
2.3.3 Exploratory Endpoints

Plasma T790M and other biomarkers related to EGFR TKI sensitivity and/or 
resistance

Plasma pharmacokinetics of ASP8273

PFS#2 on subsequent therapy

QoL and PRO parameters


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IS AMENDED TO:
2.1.2 Secondary Objectives

Overall survival (OS)

Overall response rate (ORR) as assessed by IRR

PFS as assessed by the investigator

Disease control rate (DCR) as assessed by IRR

Duration of Response (DOR) as assessed by IRR 

Safety of ASP8273

To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) 
parameters as measured by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-
QLQ-C30 and EQ-5D-5L
2.1.3 Exploratory Objectives

To evaluate potential biomarkers that may affect treatment outcome

Evaluation of the pharmacokinetics of ASP8273

To evaluate the impact of subsequent therapy on progression free survival on next-
line therapy (PFS#2)

To evaluate Quality of Life (QoL) and patient reported outcome (PRO) parameters as 
measured by FACT EGFRI 18, EORTC QLQ LC13, EORTC QLQ C30 and EQ 5D
5L.
2.3.2 Secondary Endpoints

OS

Best overall response rate (CR + PR) by IRR

PFS by the investigator

Disease control rate (CR+PR+SD) by IRR

DOR by IRR

Safety variables (e.g., AEs, laboratory tests, vital sign measurements, ECGs)

QoL and PRO parameters
2.3.3 Exploratory Endpoints

Plasma T790M and other biomarkers related to EGFR TKI sensitivity and/or 
resistance

Plasma pharmacokinetics of ASP8273

PFS#2 on subsequent therapy

QoL and PRO parameters
IV Synopsis, Planned Total Number of Study Centers and Location(s)
WAS:
Approximately 200 centers (Globally)
IS AMENDED TO:
Approximately 200 240 centers (Globally)


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IV Synopsis, Number of Subjects to be Enrolled/Randomized, Study Design Overview, 
Sample Size Justification, Interim Analysis, 2 Study Objective(s), Design, and 
Endpoints and 7 Statistical Methodology
2.2.1 Study Design, 7.1 Sample Size and 7.9 Interim Analysis
WAS:
Approximately 540 subjects
IS AMENDED TO:
Approximately 540 600 subjects
IV Synopsis, Study Design Overview and 2 Study Objective(s), Design, and Endpoints
2.2.1 Study Design 
WAS:
PFS by IRR is the primary variable. Secondary variables include OS, ORR, PFS by the 
investigator, DCR and safety.  Exploratory variables include biomarkers, pharmacokinetics, 
PFS #2 on subsequent therapy and QoL/PRO.
Arm A will receive 300 mg daily of ASP8273 and Arm B will receive either 150 mg erlotinib 
or 250 mg gefitinib daily, as decided by the investigator prior to randomization. Both arms 
will follow 28-day cycles of continuous dosing.  Subjects will be stratified according to the 
following:  ECOG PS (0, 1 or 2), EGFR mutation status (exon 19 deletion or mutations in 
exon 21 [L858R]), TKI chosen (erlotinib or gefitinib) and race (Asian versus non-Asian).
IS AMENDED TO:
PFS by IRR is the primary variable. Secondary variables include OS, ORR, PFS by the 
investigator, DCR, DOR, and safety and QoL/PRO.  Exploratory variables include 
biomarkers, pharmacokinetics, and PFS #2 on subsequent therapy and QoL/PRO.
Arm A will receive 300 mg daily of ASP8273 and Arm B will receive either 150 mg erlotinib 
or 250 mg gefitinib daily, as decided by the investigator prior to randomization for each site 
at the beginning of the trial. Both arms will follow 28-day cycles of continuous dosing.  
Subjects will be stratified according to the following:  ECOG PS (0, 1 or 2), EGFR mutation 
status (exon 19 deletion or mutations in exon 21 [L858R]), TKI chosen (erlotinib or gefitinib) 
and race (Asian versus non-Asian).
IV Synopsis, Study Design Overview, 2 Study Objective(s), Design, and Endpoints and 
5 Treatments and Evaluation
2.2.1 Study Design and 5.3 Efficacy Assessment
ADDED:
Imaging of the brain is required at baseline for all subjects, and may be repeated 
throughout the study as clinically indicated. If a brain lesion not previously irradiated is 
selected as a target lesion at baseline, the assessment should be repeated at all 
subsequent imaging timepoints. 


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IV Synopsis, Study Design Overview, Sample Size Justification, 2 Study Objective(s), 
Design, and Endpoints and 7 Statistical Methods
2.2.1 Study Design, 7.1 Sample size and 7.4.1.1 Primary Analysis
WAS:
An independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and 
the planned futility analysis which will occur after at least 181 PFS events have been 
observed. 
The primary analysis will occur when at least 362 PFS#1 events are observed which is 
expected to occur approximately 36 months after randomization. Primary endpoint, 
secondary endpoints and other endpoints will be analyzed at the time of primary analysis.
Assuming HR=0.667 (median PFS in Arm A and Arm B are 15.6 months and 10.4 months, 
respectively), a total of 362 PFS events will provide approximately 95% power to detect a 
statistically significant difference at type I error rate of 1-sided 0.025.
IS AMENDED TO:
An independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and 
the planned interim futility analysis which will occur after at least 181 210 PFS#1 events 
have been observed. 
The primary analysis will occur when at least 362 420 PFS#1 events are observed which is 
expected to occur approximately 36 months after randomization of the first subject. Primary 
endpoint, secondary endpoints and other endpoints will be analyzed at the time of primary 
analysis.
Assuming HR=0.667 (median PFS in Arm A and Arm B are 15.6 months and 10.4 months, 
respectively), a total of 362 420 PFS events will provide approximately 9598.7% power to 
detect a statistically significant difference at type I error rate of 1-sided 0.025.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.2 Inclusion Criteria No. 4, 7, 13 and 14
WAS:
4. Female subject must either:

Be of nonchildbearing potential:
o
postmenopausal (defined as at least 1 year without any menses) prior to 
Screening, or 
o
documented surgically sterile

Or, if of childbearing potential: 
o
Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration
o
And have a negative serum pregnancy test at Screening 
o
And, if heterosexually active, agree to consistently use 2 forms of highly 
effective birth control* (at least 1 of which must be a barrier method) starting 
at Screening and throughout the study period and for 28 days after the final 
study drug administration


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7. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (1 of which 
must be a barrier method) starting at Screening and continue throughout the study period 
and for 90 days after the final study drug administration.
*Highly effective forms of birth control include:

Consistent and correct usage of established oral, injected or implanted hormonal 
methods of contraception

Established intrauterine device (IUD) or intrauterine system (IUS)

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (not applicable 
in Japan)

Calendar-based contraceptive methods (Knaus-Ogino or rhythm method [Japan only])
13.  Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or 
without T790M mutation, by local or central testing on examination of a NSCLC FFPE 
specimen.  A tissue sample from the same block used to determine eligibility by local testing 
should be available to send to the central lab for confirmatory testing.
14.  Subject must have at least 1 measureable lesion based on RECIST V1.1.
IS AMENDED TO:
4. Female subject must either:

Be of nonchildbearing potential:
o
postmenopausal (defined as at least 1 year without any menses) prior to 
Screening, or 
o
documented surgically sterile

Or, if of childbearing potential: 
o
Agree not to try to become pregnant during the study and for 28 days after the 
final study drug administration
o
And have a negative serum pregnancy test at Screening 
o
And, if heterosexually active, agree to consistently use 2 forms of highly 
effective birth control* (at least 1 of which must be a highly effective 
method* and one must be a barrier method) starting at Screening and 
throughout the study period and for 28 days after the final study drug 
administration
7. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (1 of which 
must be a barrier method) starting at Screening and continue throughout the study period 
and for 90 days after the final study drug administration.
*Highly effective forms of birth control include:

Consistent and correct usage of established oral, injected or implanted hormonal 
methods of contraception

Established intrauterine device (IUD) or intrauterine system (IUS)
*Acceptable forms of birth control include:

Barrier methods of contraception: condom or occlusive cap (diaphragm or 


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cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (not applicable 
in Japan) and Thailand: with spermicidal foam/gel/film/cream/suppository)

Calendar-based contraceptive methods (Knaus-Ogino or rhythm method [Japan and 
Thailand only])
13.  Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or 
without T790M mutation, by local or central testing on examination of a NSCLC FFPE
specimen (archival or fresh biopsy)  Subjects harboring both exon 19 deletion and exon 
21 L858R mutations are not eligible. A tissue sample from the same block used to 
determine eligibility by local testing should be available to send to the central lab for 
confirmatory testing.  Subjects randomized based on local results indicating presence of 
EGFR mutations may remain on study if central results are discordant.
14.  Subject must have at least 1 measureable lesion based on RECIST V1.1.  Previously 
irradiated lesions will not be considered as measurable lesions.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.3 Exclusion Criteria No. 1, 5, 19 and 21
WAS:
1.  Subject has received intervening anticancer treatment or previous treatment with 
chemotherapy for metastatic disease.  The administration of neoadjuvant or adjuvant 
chemotherapy is allowed as long as it has finalized ≥ 6 months before the first dose of study 
drug. 
5.  Subject has symptomatic central nervous system (CNS) metastasis.  Subject with 
previously treated brain or CNS metastases are eligible provided that the subject has 
recovered from any acute effects of radiotherapy and is not requiring escalating doses of 
steroids, and any whole brain radiation therapy was completed at least 2 weeks prior to study 
drug administration, or any stereotactic radiosurgery (SRS) was completed at least 1 week 
prior to the first dose of study drug.  
19.  Subject has another malignancy which requires treatment.  
21. Subject has used the following drugs:
a. Potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug
b. Proton pump inhibitors such as omeprazole within 14 days prior to first dose of 
study drug
IS AMENDED TO:
1.  Subject has received intervening anticancer treatment or previous treatment with 
chemotherapy for metastatic disease other than palliative local radiation to painful bone 
metastases completed at least 1 week prior to the first dose of study drug.  The 
administration of neoadjuvant or adjuvant chemotherapy is allowed as long as it has finalized 
≥ 6 months before the first dose of study drug.
5.  Subject has symptomatic central nervous system (CNS) metastasis.  Subject with 
previously treated brain or CNS metastases are eligible provided that the subject has 


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recovered from any acute effects of radiotherapy, does not have brain metastasis related 
symptoms, and is not requiring escalating doses of systemic steroids, for at least 2 weeks 
prior to study drug administration, and any whole brain radiation therapy was completed 
at least 2 4 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) 
was completed at least 1 2 weeks prior to the first dose of study drug. Steroid inhaler use or 
ointment treatment for other concomitant medical disease is permitted.
19.  Subject has another past or active malignancy which requires treatment.  Prior 
carcinoma in situ or non-melanoma skin cancer after curative resection are permitted.
21. Subject has used received the following drugs:a. Potent potent CYP 3A4 inhibitors 
within 7 days prior to first dose of study drug b. or Proton proton pump inhibitors such as 
omeprazole within 14 days prior to first dose of study drug
IV Synopsis, Comparative Drug(s) Dose(s)
WAS:
Erlotinib 150 mg once daily or gefitinib 250 mg once daily as decided by the investigator. 
IS AMENDED TO:
Erlotinib 150 mg once daily or gefitinib 250 mg once daily as decided by the investigator for 
each site at the beginning of the trial. 
IV Synopsis, Dose Modifications and 5 Treatments and Evaluation
5.1.2 Increase or Reduction in Dose of the Study Drug(s) and 5.1.2.1 ASP8273 Dose 
Modification
WAS:
5.1.2 Increase or Reduction in Dose of the Study Drug(s)
Dosing for ASP8273, erlotinib or gefitinib may be interrupted or reduced (ASP8273 and 
erlotinib only) for any event if the investigator deems it necessary to ensure subject safety.  
The subject may be discontinued from treatment if there is an interruption of treatment for > 
14 days despite optimal treatment of side effects. A discussion with the Medical Monitor 
should occur to confirm if the subject should continue on study treatment.
5.1.2.1 ASP8372 Dose Modification
If a grade 3 or 4 study drug-related toxicity persists or recurs after 2 dose reductions, the 
subject should be permanently discontinued from ASP8273 treatment. Dose reescalation in 
subjects who had a dose reduction is not permitted. Additionally, if after resolution of a 
Grade 4 event requiring dose interruption and/or dose reduction, the event reoccurs at a G3 or 
higher the subject should be permanently discontinued from ASP8273.
Table 3 
ASP8273 Dose Modification
Dose level
ASP8273 dose (mg qd)
Starting dose
300
-1
200
-2
100


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IS AMENDED TO:
5.1.2 Increase or Reduction in Dose of the Study Drug(s)
Dosing for ASP8273, erlotinib or gefitinib may be interrupted or reduced (ASP8273 and 
erlotinib only) for any event if the investigator deems it necessary to ensure subject safety.  
Subjects requiring a treatment interruption should be re-evaluated not longer than 
7 days from initial interruption and restarted on study drug as soon as clinically stable. 
The subject may be discontinued from treatment if there is an interruption of treatment for 
> 14 consecutive days despite optimal treatment of side effects. A discussion with the 
Medical Monitor should occur to confirm if the subject should continue on study treatment.
In the event of acute onset or worsening of pulmonary symptoms likely suggestive of 
interstitial lung disease (dyspnea, cough, fever), study drug should be interrupted and a 
prompt investigation of these symptoms should occur and appropriate treatment 
initiated. If ILD is confirmed, study drug should be discontinued, and the subject 
should be treated appropriately per local standard of care.
Study drug should be interrupted if the subject experiences eye toxicity such as acute 
and severe eye pain or keratitis.  Subjects with suspected keratitis should have study 
drug withheld until recovery and discontinued for persistent severe keratitis.  Subjects 
with ocular toxicities should be evaluated by an ophthalmologist.
If the subject experiences severe hepatic impairment, study drug should be discontinued 
and the subject should be treated appropriately per local standard of care.
5.1.2.1 ASP8372 Dose Modification
Subjects requiring a dose reduction may be re-escalated one dose level (i.e., subjects 
reduced to 100 mg may only be re-escalated to 200 mg). If the event leading to the 
reduction recurs, the subject should be reduced to the lower dose level and not 
re-escalated again. If a grade 3 or 4 study drug-related toxicity persists or recurs after 2 dose 
reductions, the subject should be permanently discontinued from ASP8273 treatment. Dose 
reescalation in subjects who had a dose reduction is not permitted. Additionally, if after 
resolution of a Grade 4 event requiring dose interruption and/or dose reduction, the event 
reoccurs at a G3 or higher the subject should be permanently discontinued from ASP8273.
Table 3 
ASP8273 Dose Modification
Dose level
ASP8273 dose (mg qd)
Starting dose
300
-1
200
-2
100
IV Synopsis, Dose Modifications and 5 Treatments and Evaluation
5.1.2.2 Erlotinib Dose Modification
WAS:
Dose modifications for erlotinib will be implemented for toxicities of ILD, skin rash, and 
diarrhea. Subjects requiring dose reduction of erlotinib may have the dose reescalated if they 
have been on a stable dose for ≥ 3 weeks without further toxicities requiring dose 
modification and it is considered by the investigator to be in the best interest of the subject. If 
any toxicity requiring dose interruption of erlotinib recurs despite the initial dose reduction to 


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level -1 (100 mg qd), erlotinib may be reduced again to level -2 (50 mg qd). If 2 levels of 
erlotinib dose reduction are required, subsequent reescalation may only be to dose level -1. 
Table 6
Events Requiring Erlotinib Dose Modification
Erlotinib Dose Modification Criteria
Toxicity
(NCI CTCAE v4.03)
Dose Modification1 for Erlotinib
Diarrhea
Grade 1 or 2
None.  Initiate therapy with antidiarrhea medication as needed
Grade 32 or 42
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower
Rash
Grade 1
None 
Grade 2
None.  If rash persists and is intolerable or worsens over 10-14 days, then reduce by 
1 dose level and initiate treatment as outlined in protocol.
Grade 32
Reduce by 1 dose level.  If rash persists or worsens over 10-14 days, then interrupt 
erlotinib until resolution to grade 2 and then restart 1 dose level lower.
Grade 4
Permanently discontinue erlotinib
Interstitial Lung Disease
Any Grade
If ILD is suspected, erlotinib should be interrupted immediately pending diagnostic 
evaluation.  If ILD is diagnosed, erlotinib should be discontinued permanently and 
appropriate treatment instituted as necessary.
Other Toxicities 
Grade 1 or 2
None
Grade 3 2, 3
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower 
Grade 4
Permanently discontinue erlotinib
IS AMENDED TO:
Dose modifications for erlotinib are suggested for toxicities of ILD, skin rash, and 
diarrhea, however the locally approved label for erlotinib dose modification for 
toxicities should be followed. Dose modifications for erlotinib will be implemented for 
toxicities of ILD, skin rash, and diarrhea. Subjects requiring dose reduction of erlotinib may 
have the dose reescalated re-escalated if they have been on a stable dose for ≥ 3 weeks 
without further toxicities requiring dose modification and it is considered by the investigator 
to be in the best interest of the subject. If any toxicity requiring dose interruption of erlotinib 
recurs despite the initial dose reduction to level -1 (100 mg qd), erlotinib may be reduced 
again to level -2 (50 mg qd). If 2 levels of erlotinib dose reduction are required, subsequent 
reescalation may only be to dose level -1. 
Treatment with erlotinib should be used with extra caution in subjects with total 
bilirubin > 3 x ULN. Erlotinib dosing should be interrupted or discontinued if changes 
in liver function are severe such as doubling of total bilirubin and/or tripling of 
transaminases in the setting of pretreatment values outside normal range. In the setting 
of worsening liver function tests, before they become severe, dose interruption and/or 
dose reduction with frequent liver function test monitoring should be considered. 
Erlotinib dosing should be interrupted or discontinued if total bilirubin is > 3 x ULN 
and/or transaminases are > 5 x ULN in the setting of normal pretreatment value. 
Table 6
Events Requiring Erlotinib Dose Modification


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Erlotinib Dose Modification Criteria
Toxicity
(NCI CTCAE v4.03)
Dose Modification1 for Erlotinib
Diarrhea
Grade 1 or 2
None.  Initiate therapy with antidiarrhea medication as needed
Grade 32 or 42
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower
Rash
Grade 1
None 
Grade 2
None.  If rash persists and is intolerable or worsens over 10-14 days, then reduce by 
1 dose level and initiate treatment as outlined in protocol.
Grade 32
Reduce by 1 dose level.  If rash persists or worsens over 10-14 days, then interrupt 
erlotinib until resolution to grade 2 and then restart 1 dose level lower.
Grade 4
Permanently discontinue erlotinib
Interstitial Lung Disease
Any Grade
If ILD is suspected, erlotinib should be interrupted immediately pending diagnostic 
evaluation.  If ILD is diagnosed, erlotinib should be discontinued permanently and 
appropriate treatment instituted as necessary.
Other Toxicities, including ocular toxicity
Grade 1 or 2
None
Grade 3 2, 3
Interrupt erlotinib until resolution to grade 2 and then restart 1 dose level lower 
Grade 4
Permanently discontinue erlotinib
IV Synopsis, Dose Modifications and 5 Treatments and Evaluation
5.1.2.3 Gefitinib Dose Modification
WAS:
There will be no dose reductions for subjects receiving gefitinib. Below summarizes 
recommended therapy interruption for gefitinib.
Subjects with poorly tolerated diarrhea (sometimes associated with dehydration) or skin 
adverse drug reactions may be successfully managed by providing a brief (up to 14 days) 
therapy interruption followed by reinstatement of the 250 mg daily dose.
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), 
gefitinib therapy should be interrupted (up to 14 days) and a prompt investigation of these 
symptoms should occur and appropriate treatment initiated.  If ILD is confirmed, gefitinib 
should be discontinued, and the subject treated appropriately.
IS AMENDED TO:
There will be no dose reductions for subjects receiving gefitinib as it is only available as a 
single strength tablet.  Below summarizes recommended therapy interruption for gefitinib; 
however, the locally approved label should be followed for additional guidance.
Subjects with poorly tolerated diarrhea (sometimes associated with dehydration) or skin 
adverse drug reactions may be successfully managed by providing a brief (up to 14 days) 
therapy interruption followed by reinstatement of the 250 mg daily dose.
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), 
gefitinib therapy should be interrupted (up to 14 days) and a prompt investigation of these 


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symptoms should occur and appropriate treatment initiated.  If ILD is confirmed, gefitinib 
should be discontinued, and the subject treated appropriately.
Gefitinib Dose Modification Criteria
Toxicity
(NCI CTCAE 
v4.03)
Dose Modification for Gefitinib
Diarrhea
Persistent Grade 2 
or ≥ Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to 
Grade ≤1 or baseline.
Skin Reactions
≥ Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to 
Grade ≤1 or baseline.
Interstitial Lung Disease
Any Grade
In the event of acute onset or worsening of pulmonary symptoms suggestive of 
ILD (dyspnea, cough, fever), gefitinib should be interrupted immediately 
pending diagnostic evaluation.  If ILD is confirmed, gefitinib should be 
discontinued permanently and appropriate treatment instituted as necessary.
AST, ALT or bilirubin elevation
≥ Grade 2
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to 
Grade ≤1 or baseline.
Other Toxicities, including ocular toxicity
≥ Grade 3
Interrupt gefitinib up to 14 days.  Resume treatment when event resolves to 
Grade ≤1 or baseline.
If ILD, persistent severe keratitis, severe hepatic impairment or gastrointestinal 
perforation is confirmed, gefitinib should be discontinued, and the subject should be treated 
appropriately per local standard of care.
IV Synopsis, Discontinuation Criteria and 6 Discontinuation
6.1 Discontinuation of Individual Subject(s)
WAS:
The subject will be discontinued from the treatment period if any of the following occur:

Subject develops radiological progressive disease (i.e., PFS#1) per RECIST v1.1 based 
on central confirmation of investigator assessment
o
If there is radiographic evidence of PD but the investigator believes the subject is 
continuing to derive clinical benefit from study drug, the subject may remain on 
study drug until the next scheduled radiographic assessment.
o
If the next radiographic assessment confirms PD per RECIST v1.1, then the 
subject must be discontinued from study drug.
IS AMENDED TO:
The subject will be discontinued from the treatment period if any of the following occur:

Subject develops radiological progressive disease (i.e., PFS#1) per RECIST v1.1 based 
on central confirmation of investigator assessment
o
If there is radiographic evidence of PD but by investigator, however the 
investigator believes the subject is continuing to derive clinical benefit
(asymptomatic and/or without worsening of performance status or overall 


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health) from study drug, and an increase in tumor burden is not likely to 
affect vital organ function, the subject may remain on study drug until the next 
scheduled radiographic assessment which should occur after 56 days (± 7 days).
o
If the next radiographic assessment confirms indicates PD per RECIST 1.1,
which is confirmed by the central reviewer, then the subject must be 
discontinued from study drug.
o
In the rare event where PD suspected on initial assessment is not confirmed 
on subsequent scan by the investigator or central reviewer, the subject may 
continue in the study.
o
The investigator should make every effort to immediately submit 
radiographic assessments for central review when PD is either suspected or 
confirmed or uncertainty exists.
o
In case of PD determination by the investigator, however not confirmed by 
the central reviewer, and subject is progressing clinically and requires new 
anti-cancer treatment immediately, the subject should be discontinued.

Subject is required to receive local or systemic anti-cancer treatment based on 
investigator’s clinical opinion.  
IV Synopsis, Concomitant Medication Restrictions or Requirements and 5 Treatments 
and Evaluation
5.1.3 Previous and Concomitant Treatment (Medication and Nonmedication Therapy)
WAS:
Arm A (ASP8273)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
1
Chemotherapy, radiotherapy, immunotherapy, or other 
medications intended for antitumor activity 
Likely affect efficacy, safety or 
pharmacokinetics of ASP8273
2
Investigational products or therapy other than 
ASP8273
3
Potent inhibitors (e.g., ketoconazole, fluconazole, 
grapefruit or grapefruit juice) or inducers (e.g.,
rifampin, phenytoin or St. John’s wort) of CYP3A4 
ASP8273 is a substrate of CYP3A4 
4
CYP3A4 and/or P-gp substrates with a narrow 
therapeutic index1
ASP8273 may be an inhibitor of 
CYP3A4 and/or P-gp
Arm B (Erlotinib/Gefitinib)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of erlotinib/gefitinib, and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
All Subjects
Chemotherapy, radiotherapy, 
immunotherapy, or other medications 
intended for antitumor activity other than 
erlotinib/gefitinib
Likely affect efficacy, safety or 
pharmacokinetics of erlotinib or 
gefitinib
Investigational products or therapy


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Potent inhibitors (e.g., ketoconazole, 
fluconazole, grapefruit or grapefruit 
juice) or inducers (e.g., rifampin, 
phenytoin or St. John’s wort) of 
CYP3A4 
Erlotinib and gefitinib are substrates 
of CYP3A4
Proton pump inhibitors or drugs that 
cause significant elevation in gastric pH
Elevation in gastric pH may reduce 
bioavailability of erlotinib or 
gefitinib
Subjects receiving 
erlotinib
Potent/moderate inhibitors of CYP1A2 
Erlotinib is a substrate of CYP1A2
The use of the following medications should be avoided or used with caution and closely
monitored:
Medications to be Avoid or Used with Caution
Reason to be Cautious
All Subjects
Moderate/weak inhibitors or inducers of 
CYP3A4 
Erlotinib and gefitinib are substrates 
of CYP3A4
Subjects 
receiving 
gefitinib
Potent inhibitors of CYP2D6 
Gefitinib is a substrate of CYP2D6
CYP2D6 substrates with narrow 
therapeutic index1
Gefitinib is an inhibitor of CYP2D6
Warfarin
INR elevations and/or bleeding 
events have been noted in subjects 
taking warfarin while on gefitinib 
therapy
Vinorelbine
Vinorelbine taken concomitantly with 
gefitinib may exacerbate neutropenia
IS AMENDED TO:
Arm A (ASP8273)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
1
Chemotherapy, radiotherapy, immunotherapy, or other 
medications intended for antitumor activity 
Likely affect efficacy, safety or 
pharmacokinetics of ASP8273
2
Investigational products or therapy other than 
ASP8273
3
Potent inhibitors (e.g., ketoconazole, fluconazole,
grapefruit or grapefruit juice) or inducers (e.g.,
rifampin, phenytoin or St. John’s wort) of CYP3A4 
ASP8273 is a substrate of CYP3A4 
4
CYP3A4 and/or P-gp substrates with a narrow 
therapeutic index1
ASP8273 may be an inhibitor of 
CYP3A4 and/or P-gp
Arm B (Erlotinib/Gefitinib)
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of erlotinib/gefitinib, and will be strictly prohibited:
Prohibited Medications/Food
Reason to Exclude
All Subjects
Chemotherapy, radiotherapy, 
immunotherapy, or other medications 
intended for antitumor activity other than 
erlotinib/gefitinib
Likely affect efficacy, safety or 
pharmacokinetics of erlotinib or 
gefitinib


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Investigational products or therapy
Potent inhibitors (e.g., ketoconazole, 
fluconazole, grapefruit or grapefruit 
juice) or inducers (e.g., rifampin, 
phenytoin or St. John’s wort) of 
CYP3A4 
Erlotinib and gefitinib are substrates 
of CYP3A4
Proton pump inhibitors or drugs that 
cause significant elevation in gastric pH
Elevation in gastric pH may reduce 
bioavailability of erlotinib or 
gefitinib
Subjects receiving 
erlotinib
Potent/moderate inhibitors of CYP1A2 
Erlotinib is a substrate of CYP1A2
The use of the following medications should be avoided or used with caution and closely
monitored:
Medications to be Avoided or Used with Caution
Reason to be Cautious
All Subjects
Moderate/weak inhibitors or inducers of 
CYP3A4 
Erlotinib and gefitinib are substrates 
of CYP3A4
Inhibitors or inducers of P-gp
Erlotinib and gefitinib are 
substrates of P-gp
Warfarin
INR elevations and/or bleeding 
events have been noted in subjects 
taking warfarin while on gefitinib 
therapy
Subjects 
receiving 
erlotinib
Potent inhibitors of CYP1A2
Erlotinib is a substrate of CYP1A2
Subjects receiving 
gefitinib
Potent inhibitors of CYP2D6 
Gefitinib is a substrate of CYP2D6
CYP2D6 substrates with narrow 
therapeutic index1
Gefitinib is an inhibitor of CYP2D6
Warfarin
INR elevations and/or bleeding 
events have been noted in subjects 
taking warfarin while on gefitinib 
therapy
Vinorelbine
Vinorelbine taken concomitantly with 
gefitinib may exacerbate neutropenia
IV Synopsis, Statistical Methods, Efficacy
WAS:
The Full Analysis Set (FAS) will be used for the primary efficacy analysis.  All subjects who 
are randomized will be included in the FAS. For time to event endpoints including PFS and 
OS, log-rank test stratified by ECOG PS (0 and 1 combined versus 2), EGFR mutation status 
(exon 19 deletion or mutations in exon 21 [L858R]), TKI chosen (erlotinib versus gefitinib) 
will be used to compare the 2 treatment arms. The hazard ratio and corresponding 95% 
confidence interval from the stratified Cox proportional hazards regression model will also be 
presented. The median survival function will be estimated using the Kaplan-Meier method 
and will be reported along with the corresponding 95% confidence interval by treatment arm.


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IS AMENDED TO:
The Full Analysis Set (FAS) will be used for the primary efficacy analysis.  All subjects who 
are randomized will be included in the FAS. For time to event endpoints including PFS, and
OS, and DOC, log-rank test stratified by ECOG PS (0 and 1 combined versus 2), EGFR 
mutation status (exon 19 deletion or mutations in exon 21 [L858R]), TKI chosen (erlotinib 
versus gefitinib) will be used to compare the 2 treatment arms. The hazard ratio and 
corresponding 95% confidence interval from the stratified Cox proportional hazards 
regression model will also be presented. The median survival function will be estimated 
using the Kaplan-Meier method and will be reported along with the corresponding 95% 
confidence interval by treatment arm.
IV Synopsis, Interim Analyses and 7 Statistical Methods
7.9 Interim Analysis (and Early Discontinuation of the Clinical Study)
WAS:
An interim futility analysis is planned to occur after 181 PFS events are observed, which is 
expected to occur approximately 20 months after the first subject is randomized. If the 
observed HR is less than 1.1, recruitment into the study will continue as planned until 
540 subjects are recruited.  
The interim analysis will be conducted by the IDMC.  In addition safety data reviews during 
the trial will be conducted by the IDMC on a periodic basis. For example, the IDMC will 
review safety data after the first 50 patients have been treated.  The full procedures for IDMC 
safety review will be described in a separate IDMC charter.
IS AMENDED TO:
An interim futility analysis is planned to occur after 181 210 PFS events are observed, which 
is expected to occur approximately 202 months after the first subject is randomized. If the 
observed HR is less than 1.1, recruitment into the study will continue as planned until 540
600 subjects are recruited.  
The interim analysis will be conducted by the IDMC.  In addition safety data reviews during 
the trial will be conducted by the IDMC on a periodic basis. For example, the IDMC will 
review safety data after the first 50 patients have been treated randomized and on study 
drug for approximately 3 months.  The full procedures for IDMC safety review will be 
described in a separate IDMC charter.
V Flow Chart and Schedule of Assessments, Table 1 Schedule of Assessments
Footnote 10
WAS:
9  Image assessments will be done every 56 days (± 7 days), scheduled in a way to allow 
results to be available for the odd cycle day 1 visit (i.e., prior to cycles 3, 5, 7, 9 etc.).  CT 
scan with contrast (chest and abdomen) is the preferred modality for tumor assessment. 
MRI is acceptable if local standard practice or if CT scans are contraindicated in a subject 


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(e.g., subject is allergic to contrast media). All other RECIST-approved scanning methods 
such as X-ray are optional. PET-CT scans must use contrast. To ensure comparability, the 
screening and subsequent assessment of response should be performed using identical 
techniques. The same method should be employed and assessed by the same individual on 
each occasion if possible. For subjects with known brain metastases at study entry, it is 
recommended that repeat imaging also include the brain and the same methods used to 
detect brain lesions at baseline are to be used to follow the lesions throughout the study.  
Confirmation scans for CR or PR should be done at the next scheduled assessment. A 
chest x-ray or other appropriate imaging of the lungs should be performed in addition to 
specified imaging time points if a subject develops symptoms suggestive of ILD.
IS AMENDED TO:
910 Image assessments will be done every 56 days (± 7 days), scheduled in a way to allow 
results to be available for the odd cycle day 1 visit (i.e., prior to cycles 3, 5, 7, 9 etc.).  
Imaging of the brain is required at baseline for all subjects, and may be repeated 
throughout the study as clinically indicated. If a brain lesion is selected as a target 
lesion at baseline, the assessment should be repeated at all subsequent imaging 
timepoints. CT scan with contrast (chest and abdomen) is the preferred modality for 
tumor assessment. MRI is acceptable if local standard practice or if CT scans are 
contraindicated in a subject (e.g., subject is allergic to contrast media). All other 
RECIST-approved scanning methods such as X-ray are optional. PET-CT scans must use 
contrast. To ensure comparability, the screening and subsequent assessment of response 
should be performed using identical techniques. The same method should be employed 
and assessed by the same individual on each occasion if possible. For subjects with 
known brain metastases at study entry, it is recommended that repeat imaging also
Imaging assessments, including brain, should utilized include the brain and the same 
methods used to detect brain lesions at baseline are to be used to follow the lesions 
throughout the study.  Confirmation scans for CR or PR should be done at the next 
scheduled assessment. A chest x-ray or other appropriate imaging of the lungs should be 
performed in addition to specified imaging time points if a subject develops symptoms 
suggestive of ILD.
3 Study Population
3.1 Selection of Study Population
WAS:
First-line subjects with locally advanced, metastatic or unresectable stage IIIB/IV 
adenocarcinoma NSCLC (newly diagnoses or recurrent) with EGFR activating mutations 
(exon 19 deletion or exon 21 L858R) will be selected for this study.
IS AMENDED TO:
First-line subjects with locally advanced, metastatic or unresectable stage IIIB/IV 
adenocarcinoma NSCLC (newly diagnoses or recurrent) with EGFR activating mutations 
(exon 19 deletion or exon 21 L858R) will be selected for this study.  Subjects who have 
both an exon 19 deletion and exon 21 L858R mutation will not be included.


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4 Treatment(s)
4.5 Assignment and Allocation
WAS:
Randomization in a 1:1 ratio to each of the 2 treatment arms will be performed via Interactive 
Response Technology (IRT).  Randomization will be stratified by ECOG PS (0, 1 or 2), 
EGFR mutation type (exon 19 deletion or mutation in exon 21 L858R), TKI chosen (erlotinib 
versus gefitinib) and race (Asian versus nonAsian).  During screening for each subject the 
site will need to designate in IRT if the subject will receive erlotinib or gefitinib in the event 
they are randomized to the comparator arm.  Prior to the initiation of the study treatment, the 
site staff will contact the IRT in order to determine the randomly assigned treatment arm.  
Specific procedures for randomization through the IRT are contained in the study procedures 
manual.
IS AMENDED TO:
Randomization in a 1:1 ratio to each of the 2 treatment arms will be performed via Interactive 
Response Technology (IRT).  Randomization will be stratified by ECOG PS (0, 1 or 2), 
EGFR mutation type (exon 19 deletion or mutation in exon 21 L858R), TKI chosen (erlotinib 
versus gefitinib) and race (Asian versus nonAsian).  At the beginning of the trial, prior to 
site initiation and shipment of study drug supplies, each investigator will select either 
erlotinib or gefitinib to be utilized for all subjects randomized to During screening for 
each subject the site will need to designate in IRT if the subject will receive erlotinib or 
gefitinib in the event they are randomized to the comparator arm at their site.  Prior to the 
initiation of the study treatment, the site staff will contact the IRT in order to determine the 
randomly assigned treatment arm.  Specific procedures for randomization through the IRT 
are contained in the study procedures manual.
5 Treatments and Evaluation
5.1.2.1 ASP8273 Dose Modification, Table 4
WAS:
Table 4 Events Requiring ASP8283 Dose Modification
Hyponatremia
Grade 1

Recheck serum sodium levels as clinically indicated

In addition, urine osmolality, serum osmolality, and urine sodium concentrations 
should also be measured as clinically indicated

Dosing may continue without interruption at the discretion of the investigator
Grade 3

For serum sodium levels < 130 – 125 mmol/L dosing may continue at the 
discretion of the investigator with additional monitoring as noted below

For serum sodium levels < 125 mm/L interrupt dosing

Serum sodium levels, serum osmolality, urine osmolality and urine sodium 
concentrations should be measured to determine the etiology of the hyponatremia 
and continue to be drawn as clinically indicated until the serum sodium levels 
recover ≤ Grade 1 or baseline

Consider fluid management plan if clinically indicated at the discretion of the 


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investigator

Dosing should be held until serum sodium levels recover to ≤ Grade 1 or baseline, 
then dosing my resume, at the discretion of the investigator, at 1 dose level lower
Other adverse events
IS AMENDED TO:
Hyponatremia
Grade 1

Recheck serum sodium levels as clinically indicated

In addition, urine osmolality, serum osmolality, and urine sodium concentrations 
should also be measured as clinically indicated

Dosing may continue without interruption at the discretion of the investigator
Grade 2

Not defined by NCI CTCAE v4.3
Grade 3

For serum sodium levels < 130 – 125 mmol/L dosing may continue at the 
discretion of the investigator with additional monitoring as noted below

For serum sodium levels < 125 mm/L interrupt dosing

Serum sodium levels, serum osmolality, urine osmolality and urine sodium 
concentrations should be measured to determine the etiology of the hyponatremia 
and continue to be drawn as clinically indicated until the serum sodium levels 
recover ≤ Grade 1 or baseline

Consider fluid management plan if clinically indicated at the discretion of the 
investigator

Dosing should be held until serum sodium levels recover to ≤ Grade 1 or baseline, 
then dosing my resume, at the discretion of the investigator, at 1 dose level lower

If Grade > 3 hyponatremia recurs after resuming ASP8273 at a reduced dose, 
ASP8273 may be discontinued
Interstitial Lung Disease
Any grade

If ILD is suspected, ASP8273 should be interrupted immediately pending 
diagnostic evaluation. If ILD is diagnosed, ASP8273 should be discontinued 
permanently and appropriate treatment instituted as necessary.
Other adverse events, including ocular toxicity
7 Statistical Methodology
Section 7.4.2.5 Duration of Response (DOR) and 7.4.2.6 QoL and PRO Parameters
ADDED:
7.4.2.5 Duration of Response (DOR)
DOR is defined as the time from the date of the first response CR/PR (whichever is first 
recorded) as assessed by IRR to the date of radiographic progression or date of 
censoring. If a subject has not progressed, the subject will be censored at the date of last 
radiological assessment or at the date of first CR/PR if no post-baseline radiological 
assessment is available. 
The distribution of DOR will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test 
stratified by ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 
deletion or mutations in exon 21 [L858R]) and TKI chosen (erlotinib versus gefitinib). 


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Version 2.0 Incorporating Substantial Amendment 1 
In addition, stratified Cox proportional hazard model will be used to estimate the 
hazard ratio and the corresponding 95% confidence interval.
7.4.2.6 QoL and PRO Parameters
Descriptive QoL and PRO analyses will be performed on the FAS. Completion rate for 
each questionnaire will be summarized. Additional analyses will be discussed in details 
in the statistical analysis plan.
7 Statistical Methods
7.4.3.1 PFS on Next-Line Therapy (PFS#2)
WAS:
PFS on next-line therapy is defined as the time from randomization to objective tumor 
progression on next-line therapy (second progression), discontinuation of next-line treatment, 
or death from any cause, whichever comes first. 
Patients alive and for whom a second objective disease progression has not been observed 
should be censored at the last time known to be alive and without second objective disease 
progression. 
IS AMENDED TO:
PFS#2 on next line therapy is defined as the time from randomization initiation of new 
systemic anti-cancer treatment (excluding local radiation, surgical removal of 
metastatic site or protocol defined Erlotinib or Geftinib or ASP8273 based on initial 
treatment allocation per subject) to investigator-determined progression, 
discontinuation of new treatment, start of a different treatment or death from any 
cause, whichever comes first.  Otherwise, subjects will be censored. 
to objective tumor progression on next line therapy (second progression), discontinuation of 
next line treatment, or death from any cause, whichever comes first.  
Subjects who have not started new systemic anti-cancer treatment will be censored at 
Day 1.  Subjects who are alive, started new systemic anti-cancer treatment and for 
whom a PFS#2 event has not been observed should be censored at the last time known 
to be alive.  
Patients alive and for whom a second objective disease progression has not been observed 
should be censored at the last time known to be alive and without second objective disease 
progression. 
7 Statistical Methods
7.4.3.2 Other Exploratory Analyses
DELETED
In addition, analysis will be performed to evaluate Quality of Life (QoL) and PRO 
parameters as measured by FACT EGFR TKI, EORTC QLQ LC13, EORTC QLQ C30 and 
EQ 5D 5L.


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Version 2.0 Incorporating Substantial Amendment 1 
12 Appendices
12.1 List of Excluded Concomitant Medications
WAS:
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 or erlotinib/gefitinib, and will be strictly 
prohibited:
Arm A (ASP8273)

Chemotherapy, radiotherapy, 
immunotherapy or other medications 
intended for antitumor activity.

Investigational products or therapy other 
than ASP8273.

Potent inhibitors or inducers  of CYP3A4 

CYP3A4 and/or P-gp substrates with a 
narrow therapeutic index
Arm B (Erlotinib/Gefitinib)

Chemotherapy, radiotherapy, immunotherapy or 
other medications intended for antitumor 
activity other than erlotinib/gefitinib.

Investigational products or therapy.

Potent inhibitors or inducers of CYP3A4 

Proton pump inhibitors or drugs that cause 
significant elevation in gastric pH

For subjects who are administrated with 
erlotinib: 
o
Potent/moderate inhibitors of CYP1A2
Examples for excluded inhibitors, inducers and substrates for enzymes and transporters are 
provided below. This list should NOT be considered all inclusive. Investigators will consult 
individual drug labels to determine liability of the drugs.
Excluded CYP Inhibitors/Inducers
CYP3A4
Inhibitors
Potent: boceprevir, clarithromycin, conivaptan, grapefruit juice*, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole
*The effect of grapefruit juice varies widely among brands and is 
concentration-, dose- and preparation dependent.
Inducers
Potent: avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort
CYP1A2
Inhibitors
Potent: ciprofloxacin, enoxacin, fluvoxamine
Moderate: methoxsalen, mexiletine, oral contraceptives, 
phenylpropanolamine, thiabendazole, vemurafenib, zileuton
IS AMENDED TO:
The following medications/food are likely to influence evaluation of the safety, 
pharmacokinetics or efficacy of ASP8273 or erlotinib/gefitinib, and will be strictly 
prohibited:
Arm A (ASP8273)

Chemotherapy, radiotherapy, 
Arm B (Erlotinib/Gefitinib)

Chemotherapy, radiotherapy, immunotherapy or 










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Version 2.0 Incorporating Substantial Amendment 1 
[GPF v4.1]
14
SPONSOR’S SIGNATURES


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
02/19/2016 17:40:36
Clinical Study Protocol
Signature as Document Originator
Scientific Lead Approval
02/19/2016 15:31:41
Reissue v2.0, 19Feb2016
Study Manager Approval
N/A
02/19/2016 15:30:45
N/A
MGC1600213
02/21/2016 16:50:45
8273-CL-0302
2.0
Study Statistician Approval
N/A

SAP_001.pdf: 
An Open-label, Randomized Phase 3 Efficacy Study of 
ASP8273 vs Erlotinib or Gefitinib in First-line Treatment 
of Patients with Stage IIIB/IV Non-small Cell Lung 
Cancer Tumors with EGFR Activating Mutations
ISN/Protocol 8273-CL-0302
ClinicalTrials.gov Identifier: NCT02588261
Date of Statistical Analysis Plan: Final Version 2.0, dated 
11 Aug 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


An Open-label, Randomized Phase 3 Efficacy Study of 
ASP8273 vs Erlotinib or Gefitinib in First-line Treatment 
of Patients with Stage IIIB/IV Non-small Cell Lung 
Cancer Tumors with EGFR Activating Mutations
ISN/Protocol 8273-CL-0302
ClinicalTrials.gov Identifier: NCT02588261
Date of Statistical Analysis Plan: Final Version 2.0, dated 
11 Aug 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 8273-CL-0302
11-Aug-2016
Astellas
Page 1 of 56
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 11-August-2016
An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in 
First-line Treatment of Patients with Stage IIIB/IV Non-small Cell Lung Cancer Tumors with 
EGFR Activating Mutations
ISN/Protocol: 8273-CL-0302
IND number: 119,902
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 8273-CL-0302
11-Aug-2016
Astellas
Page 2 of 56
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 9
2
FLOW CHART AND VISIT SCHEDULE···················································10
3
STUDY OBJECTIVE(S) AND DESIGN······················································15
3.1
Study Objective(s) ············································································15
3.1.1
Primary Objective ·······································································15
3.1.2
Secondary Objectives ···································································15
3.1.3
Exploratory Objectives ·································································15
3.2
Study Design···················································································15
3.2.1
Study Design·············································································15
3.2.2
ASP8273 Dose/Dose Regimen and Administration Period ························17
3.3
Randomization·················································································17
4
SAMPLE SIZE·····················································································17
5
ANALYSIS SETS ·················································································18
5.1
Full Analysis Set (FAS) ······································································18
5.2
Per Protocol Set (PPS)········································································18
5.2.1
Reasons for Exclusion From PPS ·····················································18
5.3
Safety Analysis Set (SAF) ···································································19
5.4
Pharmacokinetics Analysis Set (PKAS)····················································19
5.5
Pharmacodynamics Analysis Set (PDAS)··················································19
6
ANALYSIS VARIABLES ·······································································19
6.1
Efficacy Endpoints············································································19
6.1.1
Primary Efficacy Endpoint ·····························································19
6.1.2
Secondary Efficacy Endpoints·························································20
6.1.3
Exploratory Efficacy Endpoint ························································21
6.2
Safety Variables ···············································································21
6.3
Pharmacokinetics Variables··································································24
6.4
Biomarker Variables··········································································24
6.5
Quality of Life Variables·····································································24
6.5.1
FACT-EGFRI-18········································································24
6.5.2
EORTC-QLQ-C30 ······································································24


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6.5.3
EORTC-QLQ-LC13 ····································································25
6.5.4
EQ-5D-5L ················································································25
6.6
Other Variables················································································26
7
STATISTICAL METHODOLOGY ···························································27
7.1
General Considerations·······································································27
7.2
Study Population ··············································································28
7.2.1
Disposition of Subjects ·································································28
7.2.2
Protocol Deviations ·····································································29
7.2.3
Demographic and Other Baseline Characteristics ···································29
7.2.4
Previous and Concomitant Medications ··············································30
7.2.5
Prior Anti-Cancer Drug Therapy for NSCLC········································30
7.2.6
Prior Radiation Therapy ································································30
7.2.7
Prior Cancer Surgical Procedures ·····················································30
7.2.8
Previous and Concomitant Non-Medication Therapy·······························30
7.3
Study Drugs····················································································30
7.3.1
Exposure··················································································30
7.3.2
Relative Dose Intensity ·································································30
7.4
Analysis of Efficacy ··········································································31
7.4.1
Analysis of Primary Endpoint ·························································31
7.4.2
Analysis of Exploratory Endpoint·····················································35
7.4.3
QoL/PRO·················································································36
7.5
Analysis of Safety·············································································37
7.5.1
Adverse Events ··········································································37
7.5.2
Clinical Laboratory Evaluation ························································39
7.5.3
Vital Signs················································································40
7.5.4
Electrocardiograms (ECGs)····························································40
7.5.5
Pregnancies···············································································40
7.5.6
Physical Examinations··································································41
7.5.7
ECOG Performance Status ·····························································41
7.6
Analysis of PK·················································································41
7.7
Analysis of Biomarker········································································41
7.8
Subgroups of Interest ·········································································42
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················42
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········43


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SAP Final Version 2.0
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7.10.1
Missing Data ·············································································43
7.10.2
Outliers ···················································································44
7.10.3
Visit Windows ···········································································44
7.10.4
Blinding···················································································44
8
DOCUMENT REVISION HISTORY ·························································45
9
REFERENCES ····················································································47
10
APPENDICES ·····················································································49
10.1
Appendix 1: Key Contributors and Approvers ············································49
10.2
Appendix 2: Blinding Process ·······························································52
10.3
Appendix 3: FACT-EGFR-18 Scoring Algorithm ········································53
10.4
Appendix 4: EORTC QLQ-LC13 Scoring Algorithm····································54
10.5
Appendix 5: EORTC QLQ-30 Scoring Algorithm········································55
10.6
Appendix 6: EQ-5D-5L ······································································56
List of In-Text Tables
Table 1
Schedule of Assessments·····································································11
Table 2
Post-treatment Discontinuation Schedule of Assessments ·······························14
Table 3
Laboratory Assessments······································································22
Table 4
PFS#1 Definition··············································································32
Table 5
OS Definition··················································································33
Table 6
DOR Definition ···············································································35
Table 7
PFS#2 Definition··············································································35


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 8273-CL-0302
11-Aug-2016
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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
AGP
α-acid glycoprotein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANC
Absolute neutrophil count
AntiHCV
Hepatitis C antibody
APEL
Astellas Pharma Europe Limited
APGD
Astellas Pharma Global Development
APTT
Activated partial thromboplastin time
AREC
Astellas Research Ethics Committee
AST
Aspartate aminotransferase (GOT)
AUC
Area under the curve
AUCinf
Area under the concentration – time curve from time 0 extrapolated to infinity
AUClast
Area under the concentration – time curve from time 0 up to the last quantifiable 
concentration
AUST
Astellas US Technologies
BUN
Blood urea nitrogen
CA
Competent authority
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine phosphokinase
CL/F
Apparent oral systemic clearance
CLtot
Total clearance
CNS
Central nervous system
CR
Complete response
CRF
Case report form
CRM
Continual reassessment method
CRO
Contract research organization
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
eCTD
Electronic Common Technical Document
CV
Coefficient of variation
CYP
Cytochrome P450
CYP3A4
Cytochrome P450 3A4
DCR
Disease control rate
DILI
Drug-induced liver injury
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
eGFR
Estimated glomerular filtration rate
EORTC-QLQ-
LC13
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Lung Cancer 13


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Abbreviations
Description of abbreviations
EORTC-QLQ-
C30
European Organisation for Research and Treatment of Cancer Core Quality of 
Life Questionnaire
EQ-5D-5L
EuroQol 5-Dimension 5-Level Questionnaire 
EU
European Union
FACT-EGFRI-18
Functional Assessment of Cancer Therapy – EGFRI 18 Questionnaire
FAS
Full analysis set
FFPE
Formalin Fixed Paraffin Embedded
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GWAS
Genome-Wide Association Studies
HBsAg
Hepatitis B surface antigen
Hct
Hematocrit
HDL
High density lipoprotein
Hgb
Hemoglobin
HIPAA
Health Insurance Portability And Accountability Act
HIV
Human immunodeficiency virus
HNSTD
Highest nonseverely toxic dose
HR
Hazard ratio
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICR
Imprinting control region
IDAC
Independent Data Analysis Center
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IRR
Independent radiologic review
IRT
Interactive Response Technology
ISN
International Study Number
IUD
Intrauterine device
IUS
Intrauterine system
J-NDA
Japan New Drug Application
Kinact
Inactivation rate constant
KM
Kaplan-Meier
LA
Latin America
LA-CRF
Liver abnormality case report form
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LFT
Liver function tests
LSO
Last subject out
MAA
Marketing Authorization Application
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration


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Abbreviations
Description of abbreviations
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NA
North America
NASH
Nonalcoholic steatohepatitis
NCI
National Cancer Institute
NDA
New Drug Application
NOAEL
No observed adverse effect level
NSCLC
Non-small-cell lung cancer
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PDAS
Pharmacodynamics analysis set
PET-CT
Positron emission tomography
PFS
Progression free survival
PFS#1
Disease progression on study drug
PFS#2
Progression free survival on next-line therapy
P-gp
Permeability-glycoprotein
PGx
Pharmacogenomic(s)
PHI
Protected health information
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PR
Partial response
PRO
Patient-reported outcome
PT
Prothrombin time
QTcF
Fridericia corrected QT interval
QoL
Quality of life
RBC
Red blood cell
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended phase 2 dose
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SD
Stable disease
SOC
System organ class
SOP
Standard operating procedure
STD10
Severely toxic dose in 10%
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
TLF
Tables, listings and figures
tmax
The time after dosing when Cmax occurs
TNM
TNM Classification of Malignant Tumors
TP
Total protein
ULN
Upper limit of normal
Vss
Steady state volume of distribution
Vz/F
Apparent volume of distribution


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Abbreviations
Description of abbreviations
WBC
White blood cell
WHO
World Health Organization 
List of Key Terms
Terms
Definition of terms
Baseline 
Observed values/findings which are regarded observed starting point for 
comparison.  
Enroll
To register or enter into a clinical trial.  NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.  
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study.  (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol.  Follow-up 
observations for sustained adverse events and/or survival are done in this 
period.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of substantial amount of data in an open-label 
study to ensure lack of bias. For operational efficiency an earlier time is usually targeted and 
wherever possible, the SAP should be developed in parallel with protocol finalization. For 
Phase 2-4 studies the SAP should be developed and approved before First Subject In (FSI).  
If the expected interval between FSI and soft-lock is less than 12 weeks, then the SAP should 
be approved by 12 weeks prior to the planned date of soft-lock. If needed, revisions to the 
approved SAP may be made prior to database hard lock. Revisions will be version controlled.
This statistical analysis is coordinated by the responsible biostatistician of APGD-US. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock.


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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart:


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Table 1
Schedule of Assessments
VISIT
Screening
Cycle 1
Cycle 2
Cycle 3-6
≥ Cycle 7
(odd cycles)
End of 
Treatment
Base Date
Day 1
Day 15
Day 1
Day 1
Day 1
Date of Last 
Dose
Visit Window
Day -28 to 0
±1 day
±3 days
±7 days
±7 days
+7 days
Informed Consent
X
Medical and Disease History
X
Confirmation of Eligibility
X
X
Randomization1
X
Study Drug Administration2
X
X
X
X
X
Physical Examination 3
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Biochemistry4
X
X
X
X
X
X
X
Hematology5
X
X
X
X
X
X
X
Coagulation Parameters6
X
X
X
X
X
Urinalysis7
X
X
X
X
X
X
Serum Pregnancy Test8
X
X
X
X
X
X
12-lead ECG9
X
X
X
X
X
X
X
Image Assessment10
X
X
X
Tumor Sample – EGFR11
X
Post-progression Tumor Sample (optional)12
X
Plasma Sample – EGFR 
X
X
Pharmacokinetics – Blood13
X
X
X
X
X
Plasma Sample –Biomarkers14
X
X
X
X
Whole Blood Sample – Biomarkers–
X
Whole Blood Sample for PGx (optional)
X
Concomitant Medication
X
X
X
X
X
X
X
Table continued on next page


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VISIT
Screening
Cycle 1
Cycle 2
Cycle 3-6
≥ Cycle 7
(odd cycles)
End of 
Treatment
Base Date
Day 1
Day 15
Day 1
Day 1
Day 1
Date of Last 
Dose
Adverse Event
X
X
X
X
X
X
X
Quality of Life (QoL)15
X
X
X
X
X
X
Survival Assessment
X
X
X
X
X
X
X
1
May be performed prior to C1D1 with prior sponsor approval
2
Daily dosing, 28 days per cycle
3
Physical examination and other evaluations include height (at screening only) weight, ECOG PS, and vital signs (pulse and blood pressure). Vital signs should be taken predose on 
dosing days.  The physical exam only needs to be repeated on cycle 1 day 1 if clinically significant changes from Screening (in the opinion of the investigator) are observed.
4
Biochemistry: See [Section 6.2  Table 3  for list of laboratory assessments. All biochemistry laboratory tests should be conducted after the subject has been fasting for at least 6 
hours in order to ensure accurate interpretation of glucose values. Fasting status should be recorded in source documents.  Biochemistry tests will be sent to a central laboratory for 
analysis.  Additional assessments may be done centrally or locally to monitor adverse events or as required by dose modification requirements.
5
Hematology: see [Section 6.2, Table 3] for list of laboratory assessments. Hematology tests will be sent to a central laboratory for analysis,
6
Coagulation: see [Section 6.2, Table 3] for list of laboratory assessments. Coagulation tests will be taken on day 1 of cycles 1-3 and every odd cycle thereafter (cycles 5, 7, 9 etc.).
Coagulation tests will be sent to a central laboratory for analysis.
7
Urinalysis: see [Section 6.2, Table 3] for list of urinalysis assessments. Urinalysis tests will be sent to a central laboratory for analysis.
8
For female subjects of child bearing potential only. Serum pregnancy tests every cycle where a visit takes place will be done throughout the study.
9
ECG time points are: Screening; cycle 1 day 1 predose; cycle 1 day 15 predose; and day 1 predose of cycle 2 and each subsequent cycle where a visit takes place. When collected on 
the same day, ECG should be collected prior to pharmacokinetic samples.
10 Image assessments will be done every 56 days (± 7 days), scheduled in a way to allow results to be available for the odd cycle day 1 visit (i.e., prior to cycles 3, 5, 7, 9, etc.).  
Imaging of the brain is required at baseline for all subjects, and may be repeated throughout the study as clinically indicated.  If a brain lesion is selected as a target lesion at 
baseline, the assessment should be repeated at all subsequent imaging timepoints.  CT scan with contrast (chest and abdomen) is the preferred modality for tumor assessment. MRI 
is acceptable if local standard practice or if CT scans are contraindicated in a subject (e.g., subject is allergic to contrast media). All other RECIST-approved scanning methods such 
as X-ray are optional. PET-CT scans must use contrast. To ensure comparability, the screening and subsequent assessment of response should be performed using identical 
techniques. The same method should be employed and assessed by the same individual on each occasion if possible. Imaging assessments, including brain, should utilize the same 
methods throughout the study. Confirmation scans for CR or PR should be done at the next scheduled assessment. A chest x-ray or other appropriate imaging of the lungs should be 
performed in addition to specified imaging time points if a subject develops symptoms suggestive of ILD.
Footnotes continued on next page


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11 Eligibility may be determined by a previously documented EGFR mutation test result. However, there should be sufficient tumor tissue from the specimen used to generate the 
EGFR test result to send to the central lab for confirmatory testing. If a subject does not have a previously documented EGFR mutation test result, then a fresh specimen must be 
obtained and sent to the central lab for eligibility testing. If slides are submitted, the slides should be freshly cut from the FFPE block within 18 days of sending to the central lab. A 
plasma sample for EGFR mutation detection will also be collected and submitted to the central laboratory.  
12 For subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis should be collected following local or central confirmation of 
disease progression and prior to commencement of subsequent anticancer therapy.  
13 Pharmacokinetic samples of ASP8273 will be taken for subjects randomized to Arm A (ASP8273) at predose on cycle 1 day 15 and predose on day 1 of cycles 2, 3, 5, 9 and 13 and 
at the End of Treatment visit. The date and time of each blood sample collection will be recorded to the nearest minute.  In addition, the date and time of the ASP8273 doses taken 
on the pharmacokinetic days and the last 2 ASP8273 doses taken prior to each pharmacokinetic day will be recorded to the nearest minute.  In the event ASP8273 treatment has 
been withheld for ≥3 days prior to the timepoint, the PK sample will not be collected.
14 Plasma samples for biomarkers will be collected at predose on day 1 of each odd cycle (cycles 1, 3, 5, 7, 9 etc.) and at the End of Treatment visit. Whole blood sample for 
biomarkers will be collected once at baseline.
15 QoL questionnaires are to be administered on visit days before any other scheduled assessments are conducted and before the disease status is discussed with the subject.


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Table 2
Post-treatment Discontinuation Schedule of Assessments
VISIT
Follow-up Visit
Post-treatment Follow-up
Period
Long-term Follow-up
Period
Survival Follow-up
Period
Base Date
Date of last
Dose +30 days
Every 56 days
Every 3
Months
Every 3
months
Visit Window
+7 days
±7 days
±7 days
±7 days
ECOG PS
X
Vital Signs
X
Image Assessment
X1
Subsequent therapy assessment2
X
X
X
QoL
X
QoL – EQ-5D-5L only3
X
X
Survival Assessment
X
X
X
X4
Adverse Event
X
X
1 If a subject discontinues study drug prior to radiographic disease progression (i.e., PFS#1), the subject should continue to undergo imaging assessment (including brain imaging 
when indicated and collection of tumor measurements) every 56 days (±7 days) in the posttreatment follow-up period until PFS#1 is documented per the investigator, the subject 
misses 2 or more consecutive scheduled tumor assessments, or the subject starts another cancer treatment, whichever occurs earlier.  
2 After PFS#1, subjects will be followed in the long-term follow-up period per institutional guidelines, but not less frequently than every 3 months to confirm survival status and 
collect subsequent anticancer treatment details and progression status until PFS#2 is documented or the subject starts another cancer treatment, whichever occurs earlier.  Phone 
contact with subject is sufficient for follow-up. Additional follow-up contacts may be required per sponsor request for analysis purposes.  
3 Quality of life (EQ-5D-5L only) will be assessed at each of the posttreatment or long-term follow-up survival contacts for 6 months after treatment discontinuation. QoL may be 
assessed by telephone module if follow-up contact is done by phone.
4 Subjects will be followed via phone call in the survival follow-up period approximately every 3 months to collect survival status until subject death or study closure. Additional 
follow-up contacts may be required per sponsor request for analysis purposes.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
●
To evaluate the progression free survival (PFS), based on independent radiologic review
(IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, 
metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer 
(NSCLC) with EGFR activating mutations
3.1.2
Secondary Objectives
●
Overall survival (OS)
●
Overall response rate (ORR) as assessed by IRR
●
PFS as assessed by the investigator
●
Disease control rate (DCR) as assessed by IRR
●
Safety of ASP8273
●
To evaluate Quality of Life (QoL) and patient-reported outcome (PRO) parameters as 
measured by FACT-EGFRI-18, EORTC-QLQ-LC13, EORTC-QLQ-C30 and EQ-5D-5L
3.1.3
Exploratory Objectives
●
To evaluate potential biomarkers that may affect treatment outcome
●
Evaluation of the pharmacokinetics of ASP8273
●
To evaluate the impact of subsequent therapy on progression free survival on next-line 
therapy (PFS#2)
3.2
Study Design
3.2.1
Study Design
This multinational, open-label randomized study will evaluate ASP8273 compared to 
erlotinib or gefitinib (1st generation EGFR TKI) as first line therapy in subjects with locally 
advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma NSCLC (newly 
diagnosed or recurrent) with EGFR activating mutations (exon 19 deletion or exon 21 
L858R), with or without a T790M mutation, who have not previously been treated with an 
EGFR inhibitor (1st line).
PFS by IRR is the primary variable.  Secondary variables include OS, ORR, PFS by the 
investigator, DCR, safety and QoL/PRO. Exploratory variables include biomarkers, 
pharmacokinetics and PFS#2 on subsequent therapy.
Approximately 600 subjects will be randomized 1:1 to 1 of 2 treatment arms (Arm A or 
Arm B).  Arm A will receive 300 mg daily of ASP8273 and Arm B will receive either 
150 mg erlotinib or 250 mg gefitinib daily, as decided by the investigator prior to 
randomization.  Both arms will follow 28-day cycles of continuous dosing.  Subjects will be 
stratified according to the following:  ECOG PS (0, 1 or 2), EGFR mutation status (exon 19 


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deletion or mutations in exon 21 [L858R]), TKI chosen (erlotinib or gefitinib) and race 
(Asian versus non-Asian).
Screening will take place up to 28 days prior to subject randomization on cycle 1 day 1.  
Subjects will start with cycle 1 and continue on to subsequent 28-day cycles until 1 of the 
discontinuation criteria are met.  Subjects will visit the clinic for evaluations on day 1 and 
day 15 of treatment cycle 1 and then on day 1 of subsequent treatment cycles up to cycle 7.  
Subjects who continue past cycle 7 will have visits on day 1 of each odd-numbered cycle.  
Quality of life will be assessed during each treatment cycle where a visit takes place, at the 
follow-up visit, and at each of the post-treatment or long-term follow-up survival contacts for 
6 months after treatment discontinuation (EQ-5D-5L only).
Imaging will be evaluated at baseline and every 56 days (± 7 days) throughout the study.  A 
blinded independent central reader will review all imaging scans to confirm complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) per 
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. Disease progression on study 
drug (PFS#1) should be confirmed by the blinded independent central reader before subjects 
are discontinued from treatment.  
Following discontinuation from study drug, subjects will have a follow-up visit within 
30 days after their last dose of drug for safety assessments. If a subject discontinues study 
drug prior to radiographic disease progression (i.e., PFS#1), the subject should enter the post-
treatment follow-up period and continue to undergo imaging assessments every 56 days 
(+/7 days) until PFS#1 is documented or the subject starts another anticancer treatment, 
whichever occurs earlier. 
Following PFS#1, subjects will enter the long-term follow-up period and be followed every 
3 months from the date of the follow-up visit for survival status and progression status on 
subsequent therapy (i.e., PFS#2). All subsequent anticancer therapy including date and site of 
progression for PFS#2 will be recorded on the case report form.  Subjects will be followed 
until PFS#2 is documented such as investigator-determined progression, death, subject has 
ended the subsequent anticancer therapy or the subject starts another anticancer treatment, 
whichever occurs earlier.
Following PFS#2, subjects will enter the survival follow-up period and be followed every 
3 months for survival status. 
Samples for pharmacokinetics, biomarkers and pharmacogenomics (PGx) as well as formalin 
fixed paraffin embedded (FFPE) specimens for central analysis will be collected. Eligibility 
may be determined by a previously documented EGFR mutation result. However, there 
should be sufficient tissue from the specimen used to generate the EGFR test result to send to 
the central lab for confirmatory testing. If a subject does not have a previously documented 
EGFR mutation test result, then a fresh specimen must be obtained and sent to the central lab 
for eligibility testing. From initial progression (PFS#1), an optional post-progression tumor 
tissue sample for exploratory biomarker analysis may be collected following centrally 
confirmed disease progression for subjects who sign a separate informed consent form (ICF).  


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An independent Data Monitoring Committee (IDMC) will be chartered to oversee safety and 
the planned futility analysis which will occur after at least 210 PFS events have been observed.  
The primary analysis will occur when at least 420 PFS#1 events are observed which is 
expected to occur approximately 36 months after randomization. Primary endpoint, 
secondary endpoints and other endpoints will be analyzed at the time of primary analysis.
3.2.2
ASP8273 Dose/Dose Regimen and Administration Period
ASP8273 300 mg and erlotinib 150 mg will be taken orally once daily, on an empty stomach 
defined as no food for at least 2 hours before and 1 hour after dosing, at approximately the 
same time(s) every day. 
Gefitinib 250 mg will be taken orally once daily, with or without food, at approximately the 
same time every day.
Concomitant medications should not be administered within 2 hours before or after dosing 
with ASP8273, erlotinib or gefitinib.
If a study drug dose is missed, it should be taken as soon as the subject remembers unless 
more than 12 hours has passed since the intended dosing time, in which case the subject 
should wait and take the next scheduled dose.  Subjects should not make up a missed dose by 
taking a double dose at the next scheduled dose.
3.3
Randomization
Randomization in a 1:1 ratio to each of the 2 treatment arms will be performed via Interactive 
Response Technology (IRT). Randomization will be stratified by ECOG PS (0, 1 or 2), 
EGFR mutation type (exon 19 deletion or mutation in exon 21 L858R), TKI chosen (erlotinib 
versus gefitinib) and race (Asian versus non-Asian).  During screening for each subject the 
site will need to designate in IRT if the subject will receive erlotinib or gefitinib in the event 
they are randomized to the comparator arm.  Prior to the initiation of the study treatment, the 
site staff will contact the IRT in order to determine the randomly assigned treatment arm.  
Specific procedures for randomization through the IRT are contained in the study procedures 
manual.
4
SAMPLE SIZE
Approximately 600 subjects will be randomized in a 1:1 ratio to 2 treatment arms: Arm A 
(ASP8273) and Arm B (erlotinib or gefitinib). Randomization will be stratified by ECOG PS
(0, 1 or 2), EGFR mutation type (exon 19 deletion or mutation in exon 21 [L858R]), TKI 
chosen (erlotinib versus gefitinib) and race (Asian versus non-Asian). Assuming HR=0.667 
(median PFS in Arm A and Arm B are 15.6 months and 10.4 months, respectively), a total of 
420 PFS events will provide approximately 95% power to detect a statistically significant 
difference at type I error rate of 1-sided 0.025.


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5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
Full Analysis Set (FAS) and Per Protocol Set (PPS) will be used for efficacy analysis. Safety 
Analysis Set (SAF) will be used for the analyses of safety variables. Pharmacokinetic 
Analysis Set (PKAS) will be used for pharmacokinetic analyses. The biomarker
pharmacodynamics analysis set (PDAS) will be used for all analyses of pharmacodynamics
data.
The data from all patients who were enrolled in the study will be included in the data listings. 
All enrolled subjects are those who signed the informed consent form and were assigned a 
subject number.
5.1
Full Analysis Set (FAS)
The full analysis set will consist of all subjects who are randomized.  This will be the primary
analysis set for efficacy analyses.
5.2
Per Protocol Set (PPS)
The per protocol set will consist of the subset of the FAS who do not meet criteria for PPS 
exclusion.  These criteria are to capture relevant non-adherence to the protocol. In addition, 
subjects in the PPS are required to have both baseline imaging and at least 1 post-baseline 
imaging scan. The PPS will be a secondary analysis set for efficacy analyses.  Select 
demographic and baseline characteristics may also be summarized for the PPS.
5.2.1
Reasons for Exclusion From PPS
The following reasons may lead to subject’s exclusion from PPS:
●
Entered into the study even though the subject violates the inclusion or exclusion criteria 
which may affect the assessment of the efficacy of the study drug
o
Inclusion criteria that affect efficacy are: #3, #9, #10, #12, #13 and #14.
o
Exclusion criteria that affect efficacy are: #1, #2, #3, #5, #9, #12, #18, #19 and 
#21.
For inclusion/exclusion criteria details, refer to Section 3.2 and 3.3 of the study protocol.
●
Received study treatment dose/s other than permitted by protocol for more than 14 days 
●
Administration of anti-NSCLC treatment prohibited by protocol 
●
No baseline or post-baseline imaging assessment


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5.3
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used.  The 
SAF consists of all subjects who take at least 1 dose of study medication, and will be used for 
safety analyses. 
5.4
Pharmacokinetics Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which at least one plasma concentration data is available for whom the time of dosing on the 
previous day of sampling is known. Additional subjects may be excluded from the PKAS at 
the discretion of the pharmacokineticist. Any formal definitions for exclusion of subjects or 
time-points from the PKAS will be documented in the Classification Specifications and 
determined in the Classification Meeting.
5.5
Pharmacodynamics Analysis Set (PDAS)
The biomarker pharmacodynamics analysis set (PDAS) will include the subjects from the 
SAF population for whom sufficient pharmacodynamic measurements were collected. The 
PDAS will be used for all analyses of pharmacodynamics data.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint
The primary endpoint is PFS assessed by the blinded IRR.  For each subject, PFS is defined 
as the time from the date of randomization until the date of radiological disease progression
(i.e., PFS#1) assessed by IRR, or until death due to any cause. If a subject has neither 
progressed nor died, the subject will be censored at the date of last radiological assessment or 
at the date of randomization if no post-baseline radiological assessment is available. Subjects 
who receive any further anticancer therapy for the disease before radiological progression 
will be censored at the date of the last radiological assessment before the anticancer therapy 
started. If progression or death occurs after missing 2 scheduled radiological assessments, the 
subject will be censored at the date of last radiological assessment or at the date of 
randomization if no post-baseline radiological assessment is available. Missing 2 scheduled 
imaging assessments is defined as the gap between two imaging assessments is more than 
140 days (2.5 times the scheduled imaging assessment interval (2.5 x 56 days)).
PFS (in days) is calculated as: 
(Date of death or documented Progression or censoring) – (Date of randomization) +1.
To apply the cut-off date to PFS is to exclude tumor assessments, death and anti-cancer 
therapy date after cut-off date in the analysis.
Note: Patient cannot be censored at “Not Evaluable (NE)”.  If NE is the only previous 
assessment, then PFS will be censored at Day 1.


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6.1.2
Secondary Efficacy Endpoints
6.1.2.1 Overall Survival (OS)
OS is defined as the time from the date of randomization until the documented date of death 
from any cause.  All events of death will be included, regardless of whether the event 
occurred while the subject is still taking study drug or after the subject discontinue study 
drug. Subjects who are still alive at the time of analysis will be censored at the last day 
known to be alive or at the analysis cutoff data, whichever is earlier. Subjects died after the 
analysis cut-off date will be censored at the analysis cut-off date.
OS (in days) is calculated as: 
(Date of death or known to be alive) – (Date of randomization) +1.
6.1.2.2 Objective Response Rate (ORR)
Best overall response is determined once all tumor response data for the subject is available.  
Subjects will be classified by best response on study as outlined in RECIST v1.1 criteria.    
For best overall response of stable disease (SD), SD must be documented as present at least 
once after study entry and at least 7 weeks (the minimum required days for first scheduled 
imaging assessment after first dose) after first dose.
ORR is defined as the proportion of subjects with best overall response as complete response
(CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by 
the blinded IRR.  ORR as assessed by the local investigator will be performed as a sensitivity 
analysis.
Analysis of ORR with confirmation defined as the proportion of subjects with best overall 
response as confirmed CR or confirmed PR based on the RECIST v1.1 as assessed by the 
blinded IRR may also be performed. Confirmation of CR or PR should occur at the next 
scheduled assessment (not less than 4 weeks following the initial assessment at which CR or 
PR is observed)
6.1.2.3 Disease Control Rate (DCR)
The DCR is defined as the proportion of subjects with a CR or PR (without confirmation) or 
SD based on RECIST v1.1 as assessed by the blinded IRR.  DCR as assessed by the local 
investigator will be performed as a sensitivity analysis.
Analysis of DCR with confirmation defined as the proportion of subjects with best overall 
response as confirmed CR, confirmed PR or SD  based on the RECIST v1.1 as assessed by 
the blinded IRR may also be performed.
6.1.2.4 Duration of Response (DOR)
DOR is defined as the time from the date of the first response CR/PR (whichever is first 
recorded) as assessed by IRR to the date of radiographical progression or date of censoring.  
If a subject has not progressed, the subject will be censored at the date of last radiological 
assessment or at the date of first CR/PR if no post-baseline radiological assessment is 


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available. DOR will be derived for subjects with best overall response as CR or PR (without 
confirmation).  
DOR (in days) is calculated as: 
(Date of documented progression or censoring) – (Date of the first response CR/PR) +1.
To apply the cut-off date to DOR is to exclude tumor assessments after cut-off date in the 
analysis.
6.1.2.5 PFS#1 as assessed by Local Investigator
See Section 6.1.1 for the definition of PFS#1.  Tumor assessments as assessed by local 
investigator will be used in the derivation of PFS.
6.1.3
Exploratory Efficacy Endpoint
6.1.3.1 PFS on Next-line therapy (PFS#2)
PFS#2 is defined as the time from initiation of new systemic anti-cancer treatment (excluding 
local radiation, surgical removal of metastatic site or protocol defined Erlotinib or Gefitinib 
or ASP8273 based on initial treatment allocation per subject) to investigator-determined 
progression , discontinuation of  new treatment, start of a different treatment or death from 
any cause, whichever comes first. Otherwise, subjects will be censored.
Subjects who have not started new systemic anti-cancer treatment will be censored at Day 1. 
Subjects who are alive, started new systemic anti-cancer treatment and for whom a PFS#2 
event has not been observed should be censored at the last time known to be alive.  
PFS#2 (in days) is calculated as: 
(Date of death or investigator-determined progression on next-line therapy or discontinuation 
of next-line therapy or started another therapy or censoring) – (Date of randomization) +1.
6.2
Safety Variables
Safety endpoints such as AEs, laboratory tests, vital signs, ECGs and ECOG performance 
status are secondary endpoints of the study.
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug).
o
TEAE is defined as an adverse event observed after starting administration of 
the study drug. If the adverse event occurs on Day 1 and the onset check box 
is marked “Onset after first dose of study drug” or the onset check box is left 
blank, then the adverse event will be considered treatment emergent. If the 
adverse event occurs on Day 1 and the onset check box is marked “Onset 
before first dose of study drug”, then the adverse event will not be considered 
treatment emergent. If a subject experiences an event both during the pre-


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investigational period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity (i.e. it is reported with 
a new start date). All adverse events collected that begin within 30 days after 
taking the last dose of study drug will also be counted as TEAE. Any AEs 
with onset dates completely missing will be considered TEAEs in summaries. 
AEs with partially missing onset dates will be assumed TEAEs unless the 
available portion of the date indicates that the onset was strictly before start of 
study medication.
o
A drug-related TEAE is defined as any TEAE with at least possible 
relationship (possibly or probably related) to study treatment as assessed by 
the investigator or with missing assessment of the causal relationship
●
Serious adverse events (SAEs) include adverse events that are flagged as serious by the 
investigator on eCRF, or upgraded by the Sponsor based on review of the Sponsor’s list 
of Always Serious term. 
●
Clinical laboratory variables 
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
Refer to the Schedule of Assessments for study visit collection dates. 
Additional laboratory tests should be performed according to institutional standard of care.  
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator or delegated sub-investigator who is a qualified physician.
Table 3
Laboratory Assessments
Panel/Assessment
Parameters to be analyzed 
NCI-CTCAE 
Grading 
(Hyper/Hypo)
Hematology
Hematocrit (Hct)
Hemoglobin (Hgb)
Red Blood Cell Count (RBC)
White Blood Cell Count (WBC)
WBC differential
Platelets
Mean Corpuscular Volume (MCV)
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
N/A
Both
N/A
Both
N/A
Hypo
N/A
N/A
N/A
Table continued on next page


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Panel/Assessment
Parameters to be analyzed 
NCI-CTCAE 
Grading 
(Hyper/Hypo)
Biochemistry (fasting)
Sodium (Na)
Magnesium (Mg)
Creatine Phosphokinase (CK)
Potassium (K)
Calcium (Ca)
Chloride (Cl)
Phosphate (P)
Creatinine (Cr)
Glucose (Gl)
Blood Urea Nitrogen (BUN)
Alkaline Phosphatase (ALP)
Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
Lactate Dehydrogenase (LDH)
Bilirubin Total (TBL) (total and direct)
Total Protein (TP)
Albumin (Alb)
Bicarbonate (HCO3)
Serum HCG for female subjects of childbearing 
potential
Both
Both
Hyper
Both
Both
N/A
Hypo
Hyper
Both
N/A
Hyper
Hyper
Hyper
N/A
Hyper
N/A
Hypo
N/A
N/A
Urinalysis 
Protein
Glucose
pH
Occult Blood
Ketones
Bilirubin
Urobilinogen
Sodium
Potassium
Chloride 
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Coagulation Profile
PT (sec)
APTT
INR
N/A
Hyper
Hyper
●
Vital signs (systolic and diastolic blood pressures (mmHg), radial pulse rate 
(beats/minute) and body temperature)
●
12-lead electrocardiogram (ECG)
●
ECOG performance scores 
●
Physical Examination Standard(general appearance, skin, eyes, ears, nose, throat, neck, 
cardiovascular, chest and lungs, abdomen, musculoskeletal, neurologic status, mental 
status, and lymphatic systems)


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6.3
Pharmacokinetics Variables
Plasma concentration data of ASP8273 and its metabolite(s) (if applicable) will be analyzed 
and descriptive statistics will be provided. Additional model-based analyses may be 
performed and reported separately.
6.4
Biomarker Variables
Tumor tissue sample (FFPE) will be obtained and sent for central confirmatory testing to 
evaluate for EGFR activating mutation. The sample sent for confirmatory testing should be 
from the same specimen as used for local testing for eligibility. A plasma sample will be 
collected to evaluate EGFR mutations. Plasma and whole blood samples will be collected for 
exploratory analysis of biomarkers.  An optional post-progression tumor tissue sample for 
exploratory biomarker analysis may be collected following centrally confirmed disease 
progression for subjects who sign a separate ICF.
6.5
Quality of Life Variables
Subjects will be asked to complete the QoL and PRO questionnaires electronically at baseline 
and at day 1 of each cycle where a visit takes place.
6.5.1
FACT-EGFRI-18
The Functional Assessment of Chronic Illness Therapy-EGFR Inhibitors Subscale (FACT-
EGFRI-18) is a treatment-specific subscale of the Functional Assessment of Chronic Illness 
Therapy (FACIT) measurement system specifically designed to assess the effect of EGFR 
inhibitors on quality of life. (Wagner et al). The FACT-EGFRI-18 is an 18-item Likert-scaled 
questionnaire, arranged in three HRQL dimensions: physical (seven items), social/emotional 
(six items), and functional well-being (five items).  The instrument takes less than 10 minutes 
to complete, and the recall period is the past 7 days.  The response scores ranged from 0 to 4, 
and the response categories include “not at all”, “a little bit”, “somewhat”, “quite a bit”, and 
“very much”. Negatively worded items (e.g., “My skin bleeds easily “or “My skin condition 
affects my mood”) are reverse-scored, so that participants who experience a higher impact of 
symptom burden on HRQL receive a lower score (range 0-72).
6.5.2
EORTC-QLQ-C30
The EORTC-QLQ-C30 is a 30-item cancer-specific instrument (Aaronson et al 1993). Multi-
trait scaling was used to create five functional domain scales: Physical, Role, Emotional, 
Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales 
assess Fatigue, Pain and Emesis; and six single items assess other symptoms.
Validity for EORTC-QLQ-C30 was illustrated in a study evaluating quality of life in a 
sample of NSCLC patients, where the EORTC-QLQ-C30 discriminated between participants 
in the intervention arm (186 patients undergoing adjuvant chemotherapy) and in the 
observation arm (173 patients), with significant differences in the domains of Global quality 
of life, Physical functioning, Role functioning and Social functioning showing better scores 
for the observation arm at 3 months, returning to baseline score at 9 months (Bezjak et al 
2008). In the most recent version of the instrument (version 3), the Cronbach's alpha-


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coefficients for internal consistency ranged from 0.56 to 0.85, with emotional functioning 
having the highest Cronbach's alpha-coefficient (Cankurtaran et al 2008). The EORTC-QLQ-
C30 discriminated between different types of cancers (lung, colorectal and prostate) in a 
study exploring peri-diagnostic and survival wait times (Grunfeld et al 2009). Predictive 
validity of the EORTC-QLQ-C30 was illustrated in a study with 538 cancer patients (101 had 
lung cancer) where Function and Symptom scales were predictive of overall patient 
satisfaction upon univariate analysis (Lis et al 2009).
The instrument’s evidence for the ability to detect change has been reported for NSCLC 
treatment trials (Yang et al 2013 & O’Brien et al 2004). Evidence supporting interpretation of 
scores (i.e., availability of MID estimates in patients with NSCLC) also is available 
(Maringwa et al 2011).  Like the other EORTC instruments, the recall period for items is the 
past 7 days, and response options include a 4-point Likert scales, yes/no options, or a 7-point 
scale for 2 global questions related to overall health status and HRQL. The instrument takes 
less than ten minutes to complete. The total score for the instrument ranges from 0 to 100, 
with a high score for a functional scale representing a high/healthy level of functioning and a 
high score for a symptom scale or item representing a high level of symptomatology or 
problems (Fayers et al 2001).
6.5.3
EORTC-QLQ-LC13
The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, developed in 
1994.  Module items evaluate symptoms such as cough, hemoptysis, shortness of breath, sore 
mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The developers of 
EORTC-QLQ-LC13 indicate that it is highly preferred not to use the LC13 alone (without the 
core module QLQ-C30), since the module has been designed to be used together with the 
core questionnaire, and the content validity is based upon this combination. The response 
options and scoring system are the same as for the EORTC QLQ-C30, and the administration 
is similar. The recall period for items is the past 7 days, and response options include either a 
4-point Likert scale or yes/no options. The instrument takes less than ten minutes to 
complete. The total score for the instrument ranges from 0 to 100. A high score for a 
functional scale represents a high/healthy level of functioning whereas a high score for a 
symptom scale or item represents a high level of symptomatology or problems (Fayers et al 
2001).
6.5.4
EQ-5D-5L
The EQ-5D is a generic preference-based measure that indirectly measures the utility for 
health that generates an index-based summary score based upon societal preference weights 
(Pickard et al 2007). The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual 
analog scale for health status. The utility scores allow for comparisons of disease burden to 
be made across various conditions, and the calculated quality-adjusted life years as an 
outcome for determining the cost effectiveness of health care interventions.  The index-based 
score is typically interpreted along a continuum where 1 represents best possible health and 
0 represents dead.


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6.6
Other Variables
●
Body Mass Index (BMI) 
BMI = weight (kg) / [height (m)]2
●
Duration of exposure
Duration of exposure to a study drug will be calculated in days, using the following 
formula:
(Date of last dose of study drug – Date of first dose) + 1
When the start or stop date is missing, then the exposure will be treated as missing.
●
Cumulative Actual Dose
Total amount of study drug actually taken by the patient from first dose date to last dose 
date
●
Planned Dose Intensity
Planned dose intensity for ASP8273 is 300 mg/day, for erlotinib is 150 mg/day and for 
gefitinib is 250 mg/day.
●
Actual Dose Intensity
Defined as the cumulative actual dose divided by duration of exposure 
●
Relative Dose Intensity (RDI)
Actual Dose Intensity
-----------------------------  x 100
Planned Dose Intensity
●
Duration of NSCLC
Duration of NSCLC will be calculated in days using the following formula:
(Randomization date – date of initial diagnosis of NSCLC) + 1
If the date of initial diagnosis of NSCLC is incomplete or missing, then the duration 
of NSCLC will be missing.
●
Duration of NSCLC since date of locally advanced or metastatic disease diagnosis
Duration of NSCLC since date of locally advanced or metastatic disease diagnosis will 
be calculated in days using the following formula:
(Randomization date – date of locally advanced or metastatic disease diagnosis) + 1


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If the date of locally advanced or metastatic disease diagnosis is incomplete or 
missing, then the duration of NSCLC since date of locally advanced or metastatic disease 
diagnosis will be missing.
●
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date 
of the first dose of study drug. 
Concomitant medication is defined as medication with at least one dose taken between 
the date of first dose (inclusive) and the date of last dose (inclusive) of study drug.
●
Previous and concomitant non-medication therapy
Previous non-medication therapy is defined as non-medication therapy administered at 
least once before the date of the first dose of study drug.
Concomitant medication is defined as non-medication therapy administered at least once 
between the date of first dose (inclusive) and the date of last dose (inclusive) of study 
drug.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e. will add up to 100%. 
Kaplan-Meier survival curves will be displayed for time-to-event variables and median 
survival time will be estimated with 2-sided 95% confidence interval (CI).
Summaries based on FAS and PPS (e.g. disposition, baseline and efficacy data) will be 
presented by planned treatment, unless specifically stated otherwise. Safety analysis and 
other summaries based on SAF, PKAS or PDAS will be presented by actual treatment
received. 
All statistical comparisons will be made using one sided test at the α=0.025 significance 
level unless specifically stated otherwise.  All null hypotheses will be Arm A is not better 
than Arm B, all alternative hypotheses will be Arm A is better than Arm B, unless 
specifically stated otherwise.
All data processing, summarization, and analyses will be performed using SAS® Version 9.2 
or higher on Unix. Specifications for table, figure, and data listing formats can be found in 
the TLF specifications for this study.


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Study day for safety assessments (e.g. laboratory assessment, onset of adverse events, vital 
signs, etc.) will be calculated in reference to the first dose date. For assessments conducted 
before the first dose, study day will be calculated as (assessment date – first dose date). For 
assessments conducted on or after the first dose, study day will be calculated as  (assessment 
date – first dose date + 1).
Study day for efficacy assessments (imaging assessment, overall survival, tumor response, 
etc.) will be calculated in reference to the randomization date. For assessments conducted 
before randomization, study day will be calculated as (assessment date – randomization date). 
For assessments conducted on or after randomization, study day will be calculated as   
(assessment date – randomization date + 1).
For efficacy evaluation, baseline is defined as the last available measurement before 
randomization. For safety evaluation, baseline is defined as the last available measurement 
before first dose. Unless otherwise specified, all summaries will be presented by treatment 
arm.
For the definition of subgroups of interest please refer to Section 7.8
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number and percentage of subjects with informed consent, discontinued before 
randomization, randomized (overall only);
●
Number and percentage of subjects randomized in each analysis set, by treatment group 
and overall;
●
Number and percentage of subjects discontinued treatment, by primary reason for 
treatment discontinuation, by treatment group for FAS and SAF; 
●
Number and percentage of subjects completed the 30 day follow-up visit, by primary 
reason for 30 day follow-up discontinuation for randomized subjects, by treatment 
group; 
●
Number and percentage of subjects completed or discontinued post-treatment period, by 
primary reason for post-treatment discontinuation for randomized subjects, by treatment 
group; 
●
Number and percentage of subjects completed or discontinued long term follow-up 
period, by primary reason for long term follow-up discontinuation for randomized 
subjects, by treatment group; 
●
Number and percentage of subjects completed or discontinued survival follow-up period, 
by primary reason for survival follow-up discontinuation for randomized subjects, by 
treatment group; 
●
Number and percentage of screen failure subjects, by primary reason for screen failure 
for screen failure subjects only; 
●
Number and percentage of subjects excluded from PPS by reason for exclusion defined 
in Section 5.2.1, by treatment arm for FAS.


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7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all subjects randomized. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by treatment group and overall as 
well as by study site. Subjects deviating from a criterion more than once will be counted once 
for the corresponding criterion. Any subjects who have more than one protocol deviation will 
be counted once in the overall summary. A data listing will be provided by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive statistics.
Number and percentage of subjects randomized in each country and site will be presented by 
treatment group and overall for the FAS. 
Descriptive statistics for age, weight, body mass index (BMI) and height at study entry will 
be presented. Frequency tabulations for sex, ethnicity, age group (defined in Section 7.8) and 
race will be presented. Stratification factors (ECOG performance status, TKI chosen, Race 
and EGFR status) used at randomization will also be summarized by treatment group and 
overall. In addition, summary statistics for tobacco history and number of pack years will
also be presented. This will be done for SAF, FAS, PPS, PKAS and PDAS by treatment 
group and overall.
Frequency tabulations for NSCLC disease history (primary diagnosis, most recent NSCLC 
stage, primary tumor stage, regional lymph node stage and distant metastasis) as well as the 
descriptive statistics for duration of disease (duration since initial diagnosis and duration 
since date of locally advanced or metastatic disease diagnosis) will be provided by treatment 
group and overall for FAS and SAF.
EGFR and T790 status (exon 19 deletion, exon 21 L858R and T790M mutation status) from 
local and central assessments will be summarized separately by treatment group and overall 
for FAS and SAF.
Medical history other than NSCLC and conditions existing at Baseline will be coded in 
MedDRA and summarized by System Organ Class (SOC) and Preferred Term (PT) as well as 
by PT alone, by treatment group and overall for the FAS. Baseline conditions are defined as 
those ongoing at the time of informed consent or arise following the time of informed 


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consent and before the first dose of study drug. For ongoing medical conditions, Common 
Terminology Criteria for Adverse Events (CTCAE) grade will be provided in listing.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) ,chemical subgroup (ATC 4th level) , preferred WHO name and 
route for the SAF. 
As with previous medication, concomitant medication will be summarized for each treatment 
group by therapeutic subgroup (ATC 2nd level) ,chemical subgroup (ATC 4th 
level) ,preferred WHO name and route for the SAF. Subjects taking the same medication 
multiple times will be counted once per medication and investigational period. All previous 
and concomitant medications will be coded by indication-specific ATC.
7.2.5
Prior Anti-Cancer Drug Therapy for NSCLC
Frequency tabulations of subjects with prior NSCLC drug therapy and best response to prior 
drug therapy will be presented by treatment group and overall for FAS.
7.2.6
Prior Radiation Therapy
Frequency tabulations of subjects with prior radiation therapy will be presented by treatment 
group and overall for FAS. 
7.2.7
Prior Cancer Surgical Procedures
Frequency tabulations of subjects with prior cancer surgical procedures will be presented by 
treatment group and overall for FAS. 
7.2.8
Previous and Concomitant Non-Medication Therapy
Frequency tabulations of subjects with previous and non-medication therapy and its reason 
for use will be presented by treatment group and overall for SAF.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment regimen for 
the SAF:
●
Descriptive statistics for cumulative amount of the drug subject was exposed to and 
actual dose intensity; and
●
Number and percent of subject with dose adjustments or interruptions and reasons for 
dose adjustments and interruptions by treatment regimen.
7.3.2
Relative Dose Intensity
RDI will be examined for subjects in the SAF whose total study drug count and first and last 
days of treatment are known.
RDI will be summarized in two ways for the SAF:


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●
Descriptive statistics will be presented by treatment regimen.
●
RDI will be categorized according to the following categories by treatment regimen:
o
less than 50%
o
at least 50%, less or equal to 80%
o
greater than 80%
o
Unknown.
7.4
Analysis of Efficacy 
Efficacy analyses will be conducted on the FAS and PPS. The interpretation of results from 
statistical tests will be based on the FAS. The PPS will be used to assess the robustness of the 
results from the statistical tests based on the FAS. All randomized subjects will be analyzed 
according to the treatment to which they are randomized.
7.4.1
Analysis of Primary Endpoint
The primary analysis will be performed on progression-free survival as assed by the IRR 
(PFS#1) on the FAS. In order to compare the PFS#1 between ASP8273 and the comparator 
Erlotinib/Gefitinib, the null hypothesis will be constructed:
●
H01: PFS of ASP8273 is not better than the comparator erlotinib/gefitinib
The accompanying alternative hypothesis is:
●
H11: PFS of ASP8273 is better than the comparator erlotinib/gefitinib
The primary analysis will be performed when approximately 362 PFS#1 events have been 
observed. Comparison of ASP8273 and erlotinib/gefitinib will be tested at 1-sided 
significance level of 0.025 .
The distribution of PFS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using log-rank test stratified by 
ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 vs exon 21), and TKI 
chosen (erlotinib versus gefitinib).  In addition, stratified Cox proportional hazard model will 
be used to estimate the hazard ratio and the corresponding 95% confidence interval.
The sensitivity analyses for PFS include:
●
The primary analysis repeated for PPS
●
The primary analysis including clinical progression as an event may be performed on the 
FAS
●
If there is a difference in the stratification values between IRT and the CRF, primary 
analysis may be repeated on the FAS using CRF stratification values


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●
PFS#1 as assessed by the IRR will be analyzed using restricted mean survival time
(RMST) approach from time 0 to 36 months. The restricted mean is a measure of average 
survival from time 0 to a specified timepoint. This approach does not require any model 
assumptions such as proportional hazards.
Table 4
PFS#1 Definition
Situation 
Date of Event or Censor
Outcome 
No evaluable post-baseline imaging
assessments, no death
Date of randomization
Censor 
Subject did not receive new anti-cancer therapy:
Radiographical progression documented 
per RECIST v1.1
Date of radiological PD
Event
No radiographical progression, but death 
recorded on eCRF
Date of death
Event
No radiographical progression nor death
Date of last radiological assessment 
or at the date of randomization if no 
post-baseline radiological 
assessment is available
Censor 
Subject received new anti-cancer (ACT) therapy:
Radiographical progression documented 
per RECIST v1.1 after new ACT
Date of last radiological assessment 
before start of new anti-cancer 
therapy or at the date of 
randomization if no post-baseline 
radiological assessment is available
Censor 
Radiographical progression documented 
per RECIST v1.1 before new ACT
Date of radiological PD
Event
No radiographical progression before 
new ACT but death recorded 
Date of last radiological assessment 
before start of new anti-cancer 
therapy or at the date of 
randomization if no post-baseline 
radiological assessment is available
Censor
No radiographical progression nor death
Date of last radiological assessment 
before start of new anti-cancer 
therapy or at the date of 
randomization if no post-baseline 
radiological assessment is available
Censor 
Missed 2 scheduled radiological assessments:
If radiographical progression or death 
occurs after missing 2 scheduled 
radiological assessments
Date of last radiological assessment 
or at the date of randomization if no 
post-baseline radiological 
assessment is available
Censor
PFS#1 = Date of Event or Censor – Date of Randomization +1
In addition, since it is likely that K-M curves of PFS#1 as assessed by IRR will separate late
in the study, Harrington-Fleming test will be performed as exploratory analysis with pre-
specified weight of p=0 and q=0.5. Different weights may be used as well.  


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To investigate non-proportionality between the treatment arms, the LOG(–LOG) survivor 
function versus time curves will be plotted.  The scaled Schoenfeld residuals by time plot will 
be examined for evidence of a non-zero correlation, which indicates non-proportionality. 
Piecewise Cox models may be explored given evidence of non-proportional hazards.  
Hochberg procedure will be used to control the overall error rate at 1-sided 0.025 level for 
the secondary efficacy endpoints (OS and ORR). Only when the primary endpoint 
significantly favors the ASP8273 arm will secondary endpoints be tested.
7.4.1.1 Overall Survival
The distribution of OS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test stratified by 
ECOG PS (0 and 1 combined versus 2), EGFR mutation type (exon 19 deletion or mutations 
in exon 21 [L858R]) and TKI chosen (erlotinib versus gefitinib). In addition, stratified Cox 
proportional hazard model will be used to estimate the hazard ratio and the corresponding 
95% confidence interval.
Comparison of ASP8273 and erlotinib/gefitinib will be tested at 1-sided significance level of 
0.025.  The null hypothesis will be:
●
H02: OS of ASP8273 is not better than the comparator erlotinib/gefitinib
The accompanying alternative hypothesis is:
●
H12: OS of ASP8273 is better than the comparator erlotinib/gefitinib
OS will be evaluated on the FAS and PPS.  Additional sensitivity analysis for OS will 
include:
●
If there is a difference in the stratification values between IRT and the CRF, primary 
analysis may be repeated on the FAS using CRF stratification values
Table 5
OS Definition
Situation 
Date of Event or Censor
Outcome 
Death before analysis cutoff date
Date of death
Event
Death after analysis cutoff date
Analysis cutoff date
Censor
Last known alive is before cutoff date
Last known alive date
Censor
Last known alive is after cutoff date
Analysis cutoff date
Censor
OS = Date of Event or Censor – Date of Randomization +1
To investigate non-proportionality between the treatment arms, the analyses for PFS#1 by 
IRR will be carried out for OS.
Subsequent anti-cancer therapies will be collected and summarized by treatment arm within 
drug class.  Imbalance in the use of subsequent anti-cancer therapy may potential bias the 
inference in OS.  The following methods may be used to assess the impact of the use of 
subsequent anti-cancer therapy in OS. 


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●
Censor OS at the last contact date prior to the initiation of subsequent anti-cancer 
therapy
●
Rank-preserving structural failure time method (RPSFT) to correct for confounding 
introduced by the change of treatment. The RPSFT model is based on an accelerated 
failure time model and uses a structural assumption of time-proportionality instead of 
a proportional hazards assumption as used in the Cox model
●
Inverse probability of censoring weights (IPCW).
7.4.1.2 Objective Response Rate
The comparison of ORR without confirmation as assessed by the blinded IRR between Arm 
A and Arm B will be performed using stratified CMH test. In addition, ORR for each arm 
will be estimated and corresponding 95% confidence interval will be constructed.
ORR will be assessed on the FAS.
Comparison of ASP8273 and erlotinib/gefitinib will be tested at 1-sided significance level of 
0.025.  The null hypothesis will be:
●
H03: ORR of ASP8273 is not better than the comparator erlotinib/gefitinib
The accompanying alternative hypothesis is:
●
H13: ORR of ASP8273 is better than the comparator erlotinib/gefitinib
Sensitivity analyses for ORR include:
●
Repeat the analysis on the PPS.
●
Repeat the analysis for ORR with confirmation as assessed by the blinded IRR
●
Repeat the analysis for ORR without confirmation as assessed by the local 
investigator
7.4.1.3 Disease Control Rate
The comparison of DCR without confirmation as assessed by the blinded IRR between 
Arm A and Arm B will be performed using stratified CMH test. In addition, DCR for each 
arm will be estimated and corresponding 95% confidence interval will be constructed.
DCR will be assessed on the FAS.
Sensitivity analyses for DCR include:
●
Repeat the analysis on the PPS.
●
Repeat the analysis for DCR with confirmation as assessed by the blinded IRR
●
Repeat the analysis for DCR without confirmation as assessed by the local
investigator
7.4.1.4 PFS#1 by local investigator
The distribution of PFS#1 by local investigator will be estimated on the FAS for each 
treatment arm using Kaplan-Meier methodology and compared between Arm A and Arm B 
using stratified log-rank test as specified in [Section 7.4.1].  In addition, stratified Cox 


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proportional hazard model will be used to estimate the hazard ratio and the corresponding 
95% confidence interval.
7.4.1.5 Duration of Response
The distribution of DOR will be estimated on the FAS for each treatment arm using Kaplan-
Meier methodology and compared between Arm A and Arm B using stratified log-rank test
as specified in [Section 7.4.1].  In addition, stratified Cox proportional hazard model will be 
used to estimate the hazard ratio and the corresponding 95% confidence interval.
Table 6
DOR Definition
Situation 
Date of Event or Censor
Outcome 
Subject with CR or PR (no confirmation required):
Radiographical progression documented per 
RECIST v1.1
Date of radiological PD
Event
No radiographical progression
Date of last radiological 
assessment or at the date of 
first CR or PR if no post-
baseline radiological 
assessment is available
Censor
DOR = Date of Event or Censor – Date of first CR or PR +1
7.4.2
Analysis of Exploratory Endpoint
7.4.2.1 PFS#2
The distribution of PFS#2 will be estimated on the FAS for each treatment arm using Kaplan-
Meier methodology and compared between Arm A and Arm B using stratified log-rank test
as specified in [Section 7.4.1].  In addition, stratified Cox proportional hazard model will be 
used to estimate the hazard ratio and the corresponding 95% confidence interval.
Table 7
PFS#2 Definition
Situation 
Date of Event or Censor
Outcome 
Subject did not receive new anti-cancer 
therapy
Day 1
Censor
Subject received new anti-cancer therapy:
Subject has investigator-determined 
progression on that treatment or ended that 
treatment or started another therapy or death
Minimum of [Date of 
investigator determined PD, date 
of death, new ACT end date, or 
start date of another therapy]
Event
Subject did not die nor progressed nor 
stopped the new ACT nor started another 
therapy at the time of analysis cutoff date
Last known alive date
Censor
PFS#2 = Date of Event or Censor – Date of initiation of new systemic anti-cancer treatment +1


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7.4.3
QoL/PRO
Descriptive QoL and PRO analyses will be performed on the FAS. Completion rate for each 
questionnaire will be summarized. Additional analyses will be discussed in details in a 
separate PRO SAP.
7.4.3.1 FACT-EGFRI-18
Means and standard deviations and change from baseline at each scheduled assessment will 
be reported for each of the FACT-EGFRI-18 domains (physical, social/emotional and 
functional well-being). The analyses will include data from the baseline assessment through 
the last available data.
Detailed scoring instructions for these domains are provided in Appendix 10.3   All time 
point data will be included and summarized.
7.4.3.2 EORTC-QLQ-C30
Means and standard deviations and change from baseline at each scheduled assessment will 
be reported for each of the QLQ-C30 subscales. The analyses will include data from the 
baseline assessment through the last available data.
Detailed scoring instructions for these scales are provided in Appendix 10.5   All time point 
data will be included and summarized.
7.4.3.3 EORTC-QLQ-LC13
Means and standard deviations and change from baseline at each scheduled assessment will 
be reported for each of the QLQ-LC13 subscales. The analyses will include data from the 
baseline assessment through the last available data.
Detailed scoring instructions for these scales are provided in Appendix 10.4   All time point 
data will be included and summarized.
7.4.3.4 EQ-5D-5L
Descriptive characteristics of EQ-5D-5L will be summarized from baseline assessment 
through the last available data.  Frequency and the percentage of reported problems for each 
level for each dimension will be provided.  Shift table showing shift in each dimension score 
from baseline to each post-baseline visit will be provided for the 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression). 2D bar plots will be 
generated to summarize the reported problems for each level for each dimension.
EQ-5D-5L VAS will be summarized by treatment group at each visit using descriptive 
statistics (mean, standard deviation, minimum, maximum and median). Additionally, a 
within-subject change will be calculated as the post-baseline score minus the baseline score 
and summarized in the same way. ANOVA model will be used to evaluate change from 
baseline to post-baseline visits for the EQ-5D-5L VAS including treatment as a fixed factor, 
and baseline score as a covariate. 


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Detailed scoring instructions for these dimensions are provided in Appendix 10.6   All time 
point data will be included and summarized.
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group and overall for SAF, unless 
specified otherwise. 
7.5.1
Adverse Events
For the purpose of safety assessments in this study, events recorded during the pre-
investigational period will be classified as Baseline Signs and Symptoms. All adverse event 
(AE) recorded on treatment including within 30 days from the last study treatment will be 
summarized. 
The coding dictionary for this study will be MedDRA v18.0. It will be used to summarize 
AEs by SOC and PT. AEs will be graded using National Cancer Institute’s Common 
Terminology Criteria for AEs (NCI-CTCAE). 
An overview table will include the following details by treatment group and overall:
●
Number and percentage of subjects with TEAEs,
●
Number and percentage of subjects with causally drug-related TEAEs,
●
Number and percentage of subjects with serious TEAEs and Astellas upgraded serious 
TEAE,
●
Number and percentage of subjects with serious drug-related TEAEs and Astellas 
upgraded serious drug-related TEAE,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug,
●
Number and percentage of subjects with drug-related TEAEs leading to permanent 
discontinuation of study drug, 
●
Number and percentage of subjects with grade 3 or higher TEAE 
●
Number and percentage of subjects with TEAEs leading to dose reduction,
●
Number and percentage of subjects with drug-related TEAEs leading to dose reduction,
●
Number and percentage of subjects with TEAEs leading to drug interruption,
●
Number and percentage of subjects with drug-related TEAEs leading to drug interruption, 
and
●
Number of deaths.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by treatment group and overall. Summaries will be provided for:


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●
TEAEs
●
Drug-related TEAEs, 
●
serious TEAEs and Astellas upgraded serious TEAE, 
●
drug-related serious TEAEs and drug-related Astellas upgraded serious TEAE, 
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug-related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs leading to dose reduction, 
●
Drug-related TEAEs leading to dose reduction, 
●
TEAEs leading to drug interruption, 
●
Drug-related TEAEs leading to drug interruption, 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 10% in 
any dose level, and 
●
Common TEAEs that equal to or exceed a threshold of 10% in any dose level. 
●
TEAE with CTCAE Grade 3 or higher
The number and percentage of subjects with TEAEs and TEAEs leading to death, as 
classified by PT only, will be summarized by treatment group and overall.
AE summary tables will include subject counts as opposed to AE counts. If a subject 
experiences more than one episode of a particular AE, that subject will be counted only once 
for that event. If a subject has more than one AE that code to the same preferred term, the 
subject will be counted only once for that preferred term. Similarly, if a subject has more than 
one AE within a body system, the subject will be counted only once in that body system.  
TEAEs and the number and percentage of subjects with TEAEs, as classified by SOC and PT 
will also be summarized by NCI-CTCAE severity grade and by relationship to study drug. If 
an adverse event changes in severity grade or relationship, then the subject will be counted 
only once with the worst severity grade and highest degree of relationship. The adverse event 
however will be presented in each category they were classified to. If a subject has an event 
more than once with missing severity grade/relationship and with non-missing severity grade, 
then the subject will be counted as the highest non-missing grade. If a subject has an event 
more than once with missing relationship and with non-missing relationship, then the subject 
will be counted as missing. Drug-related TEAEs will be presented in a similar way by 
severity only.
The exposure adjusted subject incidence rates of adverse events may be compared between 
treatment groups for selected categories of adverse events. The exposure adjusted subject 
incidence (subjects/subject-year) is defined for any particular adverse event as the number of 
subjects in a treatment group that experienced the specific event at least once divided by the 
total amount of time (100 subject-year) the subjects in the treatment group have been exposed 


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to the study drug.  For subjects that experience the event, their exposure time will be 
calculated as the time between the first dose date up to the initial occurrence of the event.  
For subjects who do not experience the event, their exposure time will be calculated as the 
time between the first dose date through 30 days after the last dose date, the date of death, or 
the end of study date, whichever is earlier.  For subjects that experience multiple events, their 
exposure time will be calculated up to the onset of the first event.  
The number and percentage of subjects with treatment-emergent adverse events of interest, as 
classified by SOC and PT will also be summarized by treatment group and overall. The list of 
adverse events of interest to be summarized may change during the course of the study due to 
ongoing pharmacovigilance.  It will be finalized before the database hard lock.
All AEs, deaths, SAEs and withdrawals due to adverse events will be displayed in listings. 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
7.5.2
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration.  
Selected quantitative clinical laboratory variables, i.e. hematology, biochemistry, coagulation 
and urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median by treatment group at each visit. Additionally, a within-subject change will be 
calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Changes in laboratory values will be summarized for baseline 
values versus minimum, maximum and last post-baseline values. Plots of median lab values 
at each scheduled assessment time by treatment group may be provided for each laboratory 
parameter.
Frequency tabulations of selected qualitative clinical laboratory variables (i.e. urinalysis) will 
be presented by treatment group at each visit. 
Laboratory results will also be graded using NCI-CTCAE, where possible. Parameters that 
have criteria available for both low and high values, i.e., hypo- and hyper-, will be 
summarized for both criteria. The same subject can be counted for both values if the subject 
has different laboratory values meeting each criterion. NCI-CTCAE grade of laboratory 
evaluations will be summarized by number and percentage of subjects for each visit. Shift 
tables of NCI-CTCAE grade change from baseline to worst post-baseline grade for selected 
laboratory parameters will also be presented.
The list of laboratory parameters to be summarized may change during the course of the 
study due to ongoing pharmacovigilance.  It will be finalized before the database hard lock.
Laboratory data will be displayed in listings. 


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7.5.2.1 Liver Enzymes and Total Bilirubin
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
investigational period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 8xULN
AST
> 3xULN
> 5xULN
> 8xULN
ALT or AST
> 3xULN
> 5xULN
> 8xULN
Total Bilirubin 
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin >= 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
enzymes and total bilirubin during the investigational period will be presented by treatment 
group.
7.5.3
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate and body 
temperature) will be summarized using mean, standard deviation, minimum, maximum and 
median by treatment group and visit. Additionally, a within-subject change will be calculated 
per visit as the post-baseline measurement minus the baseline measurement and summarized 
by treatment group and visit.  
7.5.4
Electrocardiograms (ECGs)
Number and percentage of subjects with normal and abnormal results as assessed locally for 
the overall interpretation will be tabulated by treatment group at each treatment visit and time 
point. 
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.


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7.5.6
Physical Examinations
A listing of physical examination results will be produced.
7.5.7
ECOG Performance Status
Summary statistics (number and percent of subjects) for each category of the ECOG 
performance status at each assessment will be provided.  The change from baseline to final 
visit or early termination will also be summarized.  Negative change scores indicate an 
improvement.  Positive scores indicate a decline in performance.
Time to deterioration from baseline in ECOG performance status defined as the change in 
score from 0 to 2 (or worse) or 1 to 2 (or worse) or 2 to 3 (or worse) will also be summarized.
The time to deterioration will be calculated  in reference to the randomization date.
7.6
Analysis of PK
PK analysis will be conducted on the PKAS. 
Plasma concentrations of ASP8273 and its metabolite(s) (if applicable) will be summarized 
for Arm A (ASP8273 arm) and where appropriate by nominal time points using descriptive 
statistics, including number of subjects, mean, standard deviation, minimum, median, 
maximum, geometric mean, and coefficient of variation (CV).
7.7
Analysis of Biomarker
Selected efficacy endpoints will be summarized for the following groups:
o
EGFR mutation detected by local and central assessments
o
EGFR mutation detected by central assessment but not local
Additional potential biomarkers that may affect treatment outcome will be explored and 
analyses details will be defined in a separate biomarker analysis plan.


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7.8
Subgroups of Interest 
PFS#1 by IRR, OS, DOR  and ORR by IRR will be summarized for the subgroups defined on 
the basis of the categorized variables listed below:
Grouping variable
Subgroups
Age group 
< 65 years
>=65 years - <75years
>=75 years
Sex
Female
Male
Race
Asian
Non-Asian
ECOG status at baseline
0 and 1
2
EGFR status
Exon 19 Deletion
Exon 21 L858R
TKI chosen
Erlotinib
Gefitinib
Additional analyses may be performed to explore treatment outcome between ECOG status at 
baseline scores 0 and 1. Forest plots for PFS#1 by IRR and OS will be produced to 
summarized the treatment effect across subgroups. PFS#1 by IRR, OS, DOR  and ORR by 
IRR may also be summarized using three treatment arms (i.e. ASP8273, Erlotinib and 
Gefitinib).
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim futility analysis is planned to occur after 210 PFS events are observed, which is 
expected to occur approximately 22 months after the first subject is randomized. If the 
observed HR is less than 1.1, recruitment into the study will continue as planned until 
600 subjects are recruited.  If the observed HR at the interim is larger than 1.1, recruitment 
into the study may be stopped at the interim analysis. Further review of the efficacy data, 
including secondary endpoints, will be performed by the sponsor to determine whether other 
evidence of clinical benefit justifies reopening enrollment. If the data do not justify reopening 
enrollment, enrollment may remain closed, and a decision will be made by the sponsor 
regarding termination of the study.  If the futility analysis takes place after enrollment is 
completed and the HR is greater than 1.1, subjects who in the opinion of the investigator and 
the sponsor’s Medical Monitor are continuing to derive benefit may continue to receive study 
drug as randomized.  As the interim analysis is for futility only, type I error at final analysis 
will not be affected.


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The interim analysis will be conducted by the IDMC.  In addition safety data reviews during 
the trial will be conducted by the IDMC on a periodic basis. For example, the IDMC will 
review safety data after the first 50 patients have been randomized plus 3 months.  The full 
procedures for IDMC safety review will be described in a separate IDMC charter.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.10.1
Missing Data 
Every effort will be made to resolve missing or incomplete dates for adverse events and 
concomitant medications. If a partial date cannot be resolved, the most conservative 
imputation methods will be used to complete the missing information. 
Missing or partial start and stop dates of adverse events, non-medication therapy and 
concomitant medication will be imputed using the following algorithm:
●
Imputation rules for partial or missing stop dates:
o
If the month and year are present, then impute as the last day of that month. 
o
If only the year is present, impute as December 31 of that year.
o
If the stop date is entirely missing, assume the event or medication is ongoing.
●
Imputation rules for partial or missing start dates:
Start Date
Stop Date
Complete: yyyymmdd
Partial: yyyymm
Partial: yyyy
Missing
< 1st
dose
≥ 1st
dose
< 1st dose 
yyyymm
≥ 1st dose 
yyyymm
< 1st dose 
yyyy
≥ 1st
dose 
yyyy
Partial: 
yyyymm
= 1st dose 
yyyymm
2
1
2
1
n/a
1
1
≠ 1st dose 
yyyymm
2
2
2
2
2
Partial: 
yyyy
= 1st dose 
yyyy
3
1
3
1
n/a
1
1
≠ 1st dose 
yyyy
3
3
3
3
3
Missing
4
1
4
1
4
1
1
1 = Impute as the date of first dose; 2 = Impute as the first of the month; 3 = Impute as January 1 of the year; 
4 = Impute as January 1 of the stop year
The imputed dates will be used to determine whether an AE is/is not treatment emergent. 
Listings of AEs, non-medication therapy and concomitant medications will present the actual 
partial dates; imputed dates will not be shown.
For secondary endpoint OS, missing or incomplete death date will be imputed as the earliest 
feasible date on or after the date last known to be alive as the examples shown in the table 
below.


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Incomplete Date of Death
(YYYY MMM  DD)
Date Last Know to be Alive
(YYYY MMM  DD)
Imputed Date of Death
(YYYY MMM  DD)
2005 APR ??
2005 MAR 31
2005 APR 01
2005 ??? 13
2005 MAR 31
2005 APR 13
2005 ??? ??
2005 MAR 31
2005 MAR 31
???? APR ??
2005 MAR 31
2005 APR 01
???? APR 13
2005 MAR 31
2005 APR 13
???? ??? ??
2005 MAR 31
2005 MAR 31
7.10.2
Outliers
All values will be included in the analyses.
7.10.3
Visit Windows
Not applicable. Nominal visits will be used in the by visit summary. Values from 
unscheduled visits will be included in the summary of extreme cases (e.g. summary of worst 
post-baseline, summary of minimum post-baseline, summary of maximum post-baseline).  
For efficacy endpoints, all values (scheduled and unscheduled) will be included in the 
analysis.
7.10.4
Blinding
Although the study is an open label study, to increase the credibility of study results, the 
sponsor statistician’s access to the randomized treatment assignment information will be 
limited.  This will help reduce potential bias due to the sponsor knowing the treatment effect 
due to unintentional efficacy and safety summary by treatment.  The following procedures 
will be implemented in this study:
●The randomized treatment code will not be transferred to statistical programmers, 
study statistician and supporting statisticians before the database lock. Datasets with 
scrambled treatment code will be transferred to prepare analysis programs.
●The study statistician, supporting statisticians and statistical programmers will have 
no direct access to the randomized treatment information before the database lock.
●Study managers and other study team members may have the access to the treatment 
information at the individual subject level.
●No treatment difference will be summarized during the study, except planned interim 
analysis or by IDMC request.


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8
DOCUMENT REVISION HISTORY
Version
Date
Changes
Comment/rationale for 
change
1.0
02-Oct-2015
NA
Document finalized
2.0
24-Jun-2016
Section 2: Flow chart
Table 1 and Table 2: Schedule of 
assessment
Sections 3.1.2, 3.1.3 and 3.2.1
-
Quality of Life (QoL) was 
moved from an exploratory 
to a secondary endpoint.
Section 4
-
Sample size and number of 
events required was changed 
to 600 and 420, respectively.
Section 7.10
-
Updated the sample size and 
the number of events required 
for the interim analysis
Changes were made to align 
the SAP with the protocol 
version 2.0
Section 6.6
Provided  additional text on how to 
handle duration variables when the 
date is incomplete or missing
Added definition of previous and 
concomitant non-medication therapy
To clarify the rule in duration 
derivation when dates are 
incomplete or missing and also 
clarify the definition of 
previous and concomitant non-
medication therapy.
Section 7.1
Provided additional text in derivation 
of study day and baseline
To provide guidance on how to 
derive study day and baseline 
since different reference date 
will be used for safety and 
efficacy assessments
Section 7.4.1
Added sensitivity analysis and 
exploratory analysis to the primary 
endpoint (PFS#1 as assessed by IRR)
Late separation of survival 
curves is expected to occur
Section 7.4.1.1
Added sensitivity analysis and 
exploratory analysis to overall survival
To investigate the potential 
effect of subsequent therapies 
on overall survival
Section 7.5.1
Added additional summaries for 
adverse events
Adverse events leading to dose 
reduction and drug 
interruptions are important 
safety information
Section 7.5.7
Added text in time to deterioration 
derivation
Provided clarification 
regarding the reference date to 
be used for time to 
deterioration


Sponsor: Astellas Pharma Global Development, Inc.
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Page 46 of 56
Version
Date
Changes
Comment/rationale for 
change
Section 7.2.4
Added a text to clarify the coding 
process for concomitant medication
Concomitant medications will 
be coded by indication-specific 
ATC
Section 7.2.8
New section for previous and 
concomitant non-medication therapy
Added section on how to 
summarize previous and 
concomitant non-medication 
therapy


Sponsor: Astellas Pharma Global Development, Inc.
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Page 47 of 56
9
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez N, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. Mar 3 1993;85(5):365-76.
Alan Agresti (1990). Categorical data analysis. New York: Wiley.
Bezjak A, Lee CW, Ding K, Brundage M, Winton T, Graham B, et al. Quality-of-life outcomes for 
adjuvant chemotherapy in early-stage non-small-cell lung cancer: results from a randomized 
trial, JBR.10. J Clin Oncol. Nov 1 2008;26(31):5052-9.
Clopper CJ, Pearson, ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial, Biometrika, 1934;26(4):404-13.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz D, Ford R, Dancey J, et al.  New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45(2):228-47.
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A on behalf of the EORTC 
Quality of Life Group. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels: EORTC, 
2001.
Grunfeld E, Watters JM, Urquhart R, O’Rourke K, Jaffey J, Maziak DE, et al. A prospective study of 
peri-diagnostic and surgical wait times for patients with presumptive colorectal, lung, or 
prostate cancer. Br J Cancer. Jan 13 2009;100(1):56-62.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika, 
1988;75(4):800-2.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Lis CG, Rodeghier M, Grutsch JF, Gupta D. Distribution and determinants of patient satisfaction in 
oncology with a focus on health related quality of life. BMC Health Serv Res. 2009;9:190.
Maringwa JT, Quinten C, King M, Ringash J, Osoba D, Coens C, et al. Minimal important differences 
for interpreting health-related quality of life scores from the EORTC QLQ-C30 in lung cancer 
patients participating in randomized controlled trials. Support Care Cancer. Nov 
2011;19(11):1753-60.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, et al. Updated overall survival 
results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin 
plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer 
harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol. 
2012;30(suppl;abstr 7521).


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Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin 
plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the 
epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. 
Lancet Oncol. 2010;11:121-8.
O'Brien ME, Anderson H, Kaukel E, O’Byrne K, Pawlicki M, Von Pawel J, et al. SRL172 (killed 
Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without 
affecting survival, in patients with advanced non-small-cell lung cancer: phase III results. Ann 
Oncol. Jun 2004;15(6):906-14.
Pickard AS, Wilke CT, Lin HW, Lloyd A. Health Utilities Using the EQ-5D in Studies of Cancer.
PharmacoEconomics 2007;25:365–84
Wagner LI, Berg SR, Gandhi M, Hlubocky FJ, Webster K, Aneja M, et al. ME. The development of a 
Functional Assessment of Cancer Therapy (FACT) questionnaire to assess dermatologic 
symptoms associated with epidermal growth factor receptor inhibitors (FACT-EGFRI-18). 
Support Care Cancer. Apr 2013;21(4):1033-41
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line 
treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer 
(OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet 
Oncol. 2011;12:735-42.








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10.2
Appendix 2: Blinding Process
As specified in SAP Section 7.10.4, although the study is an open label study, to increase the 
credibility of study results, the sponsor statistician’s access to the randomized treatment 
assignment information in study database will be limited.  This will reduce potential bias due 
to the sponsor knowing the treatment effect due to unintentional efficacy and safety summary 
by treatment. 
For the purpose of controlling unintentional assessment of efficacy and safety summary by 
treatment, the study statisticians and programmers will have no access to treatment codes 
until the time of final database lock (DBL). For this study, treatment codes can be obtained 
from two sources: IRT vendor and EDC system. The following procedures should be applied 
when handling data extraction, data transferring and TLFs preparation to maintain the 
blinding during the entire study conducting period before the final DBL.
●
The treatment codes collected in EDC system will not be extracted until the final 
DBL. The treatment variable will be blocked during any data extraction before the 
final DBL. The option for blocking treatment variable will be set up before the first 
data extraction.
●
Dummy treatment codes will be created by study programmers for preparing the 
SDTM, ADaM and TLFs for interim analysis validation and final data analysis.
●
Raw data (SDTM/ADAM if needed) without treatment codes (or with dummy codes) 
will be provided by the study team to IDAC to conduct interim analysis or other DMC 
requested analysis.
●
Separate IRT transfer requests will be sent directly by independent statistician to IRT 
vendor for transferring treatment codes to IDAC during the formal interim analysis or 
other DMC requested analysis.   
●
PK data will be transferred upon request during interim analysis and will be 
transferred directly from PK vendor to IDAC.
Study manager and other study team members may have the access to the treatment 
assignment information at the individual subject level. Dosing or other information which 
may relate to treatment assignment will not be blinded at the individual subject level due to 
operational considerations. Efficacy and safety information will not be summarized by 
treatment during the study, except at the planned interim analysis or other DMC requested 
analysis conducted by IDAC.


Sponsor: Astellas Pharma Global Development, Inc.
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Page 53 of 56
10.3
Appendix 3: FACT-EGFR-18 Scoring Algorithm
Functional Assessment of Cancer Therapy – EGFR Inhibitors (FACT-EGFRI 18)
Scoring Guidelines
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered.  This produces the symptom index score.
4. As with all FACIT questionnaires, a high score is good. Therefore, a score of “0” is a 
severely symptomatic patient and the highest possible score is an asymptomatic patient.
Scale
Item Code
Reverse item?
Item response
Item Score
FACT-EGFRI
ST4
4
-
________
=________
ST5
4
-
________
=________
ST6
4
-
________
=________
ST7
4
-
________
=________
ST9
4
-
________
=________
ST32
4
-
________
=________
ST22
4
-
________
=________
ST17
4
-
________
=________
ST24
4
-
________
=________
ST37
4
-
________
=________
ST26
4
-
________
=________
ST34
4
-
________
=________
ST38
4
-
________
=________
ST16
4
-
________
=________
ST15
4
-
________
=________
ST29
4
-
________
=________
B5
4
-
________
=________
ST11
4
-
________
=________
Sum individual item scores: ________  
Multiply by 18:  ________
Divide by number of items answered:  ________= FACT-
EGFRI score
Score range: 0-72


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Page 54 of 56
10.4
Appendix 4: EORTC QLQ-LC13 Scoring Algorithm




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10.6
Appendix 6: EQ-5D-5L