A Single Arm Phase II Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Sponsor: Duke University

 
 
1 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
A Single Arm Phase II Study: Osimertinib in Patients with Stage 4   
Non-small Cell Lung Cancer with Uncommon EGFR Mutations  
Thoracic Oncology Program (TOP) Protocol Number: TOP 1703 
 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Astra-Zeneca 
 
 
Protocol Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00088376 
 
 
IND#:  137943  
EXEMPT 
ClinicalTrials.gov 
NCT#: 03434418 
 
Principal Investigator 
Thomas E. Stinchcombe MD 
Duke Cancer Institute 
Thoracic Oncology 
Durham, NC 27710 
919.681.9509 
Fax: 919.684.5163 
thomas.stinchcombe@duke.edu 
 
Sub-Investigator(s) 
Duke Cancer Institute: 
Neal Ready, MD, PhD 
Jeffrey Clarke, MD 
Jeffrey Crawford, MD 
Jennifer Tenhover, ANP 
Yeshu Conn, ANP 
Susan Blackwell, PA-C 
Deborah Ballard, ANP 
 
 
Gregory Otterson, MD 
The Ohio State University 
Columbus, OH 
otterson.1@osu.edu 
 
 
Statistician 
Xiaofei, Wang, PhD 
Department of Biostatistics 
Duke Cancer Institute 
Durham, NC 27710 
xiaofei.wang@duke.edu 
 
Lead Study Coordinator 
Lauren “Beth” Leith, RN, 
BSN 
Thoracic Oncology 
Fax: 919.660.9246 
beth.leith@duke.edu 
 
Regulatory Coordinator 
Candice Singletary, MA 
Thoracic Oncology 
candice.singletary@duke.edu 
 
Data Management 
Thoracic Oncology Clinical 
Trials 
Room 00541, Duke South 
Duke Cancer Institute 
Durham, NC 
 
 
 
V1.0-January 30, 2018 
 
 
V2.0-1 May 2018 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
 
Statement of Compliance and Signature Page 
 
STUDY TITLE:  A Single Arm Phase II Study: Osimertinib in Patients with Stage 4   
Non-small Cell Lung Cancer with Uncommon EGFR Mutations 
 
 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Boards of Duke University Health System and The Ohio State University, according to 
Good Clinical Practice standards. No deviation from the protocol will be implemented without 
the prior review and approval of the IRB except where it may be necessary to eliminate an 
immediate hazard to a research subject. In such case, the deviation will be reported to the IRB as 
soon as possible. The signature below constitutes the approval (by the PI) of this protocol and the 
attachments, and provides the necessary assurances that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and according 
to local and state legal and regulatory requirements and applicable U.S. federal regulations and 
ICH guidelines. 
 
 
 
 
Duke Sponsor Investigator:  Thomas Stinchcombe, MD 
Duke University Thoracic Oncology Program 
 
 
 
__________________________________________    _____________ 
Thomas Stinchcombe, MD,   
 
 
    Date 
Duke Sponsor Investigator             
 
  
__________________________________________    _____________ 
Site Principal Investigator                                           Date 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................................... 7 
STUDY SCHEMA..................................................................................................................................... 9 
1.0 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ........................................................... 10 
1.1 
Protocol Synopsis ...................................................................................................................... 10 
1.2 
Research Summary .................................................................................................................... 10 
2.0 BACKGROUND AND SIGNIFICANCE ....................................................................................... 11 
2.1 
Disease Background .................................................................................................................. 11 
2.2 
Study Agent ............................................................................................................................... 13 
2.3 
Preclinical and Clinical Trial Data ............................................................................................ 13 
2.4 Clinical safety and Rationale for Dose Selection, Regimen, and Treatment Duration .................. 21 
3.0 STUDY RATIONALE .................................................................................................................... 25 
3.1 
Trial Summary ........................................................................................................................... 25 
3.2 
Design and Procedure ................................................................................................................ 25 
3.3 
Selection of Subjects ................................................................................................................. 25 
3.4 
Duration of Study ...................................................................................................................... 25 
4.0 OBJECTIVES AND ENDPOINTS ................................................................................................. 27 
5.0 SUBJECT ELIGIBILITY .................................................................................................................. 28 
5.1 Inclusion Criteria ........................................................................................................................... 28 
5.2 Exclusion Criteria .......................................................................................................................... 29 
5.2 Protocol Eligibility Waivers .......................................................................................................... 30 
6.0 INCLUSION of WOMEN and MINORITIES .................................................................................. 30 
7.0 REGISTRATION PROCEDURE ...................................................................................................... 31 
7.1 Registration for Outside Sites ........................................................................................................ 31 
8.0 STUDY PERIODS (Visit Requirements): ......................................................................................... 32 
8.1 Screening........................................................................................................................................ 34 
8.2 On-Study Treatment Period:  Day 1 of each cycle or as noted in Table 4 .................................... 34 
8.3 End of Study Treatment (30 days (+/- 3 days) after study therapy stops) ..................................... 35 
8.4 Follow-up Period ........................................................................................................................... 35 
8.5 End of Study .................................................................................................................................. 35 
8.6 Study Assessments ......................................................................................................................... 35 
8.6.1 Medical History .............................................................................................................................. 35 
8.6.2 Physical Exam ................................................................................................................................. 36 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
9.0 INVESTIGATIONAL THERAPY .................................................................................................... 36 
9.1 Study Therapy ................................................................................................................................ 36 
9.1.1 Dose Modification .......................................................................................................................... 37 
9.1.2 Management of adverse effects ...................................................................................................... 38 
9.1.3  Definition of Evaluable Subjects, On Study, and End of Study ................................................ 41 
9.1.4 Early Study Termination ............................................................................................................. 42 
10.0 BLINDING ...................................................................................................................................... 42 
11.0 CONCOMITANT MEDICATIONS ............................................................................................... 42 
12.0 OTHER CONSIDERATIONS......................................................................................................... 42 
12.1 Contraception ............................................................................................................................... 42 
12.1 Use in Pregnancy ......................................................................................................................... 43 
12.3  Use in Nursing Women ............................................................................................................... 43 
12.4 Fertility ......................................................................................................................................... 43 
13.0 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA .................................................. 44 
13.1 Criteria for Early Withdrawal ...................................................................................................... 44 
13.2 Follow-up Requirements for patients who discontinue therapy prior to disease        
progression ........................................................................................................................................... 44 
13.3 Replacement of Early Withdrawal(s) ........................................................................................... 44 
13.4 Clinical Criteria for Early Trial Termination ............................................................................... 45 
13.5 Discontinuation of the Study ....................................................................................................... 45 
14.0 STUDY DRUG ................................................................................................................................ 45 
14.1 Names, Classification, and Mechanism of Action ....................................................................... 45 
14.2 Packaging and labeling ................................................................................................................ 45 
14.3 Supply, Receipt, and Storage ....................................................................................................... 46 
14.4 Dispensing and Preparation ......................................................................................................... 46 
14.5 Compliance and Accountability ................................................................................................... 46 
14.6 Disposal and Destruction ............................................................................................................. 46 
15.0 COSTS TO THE SUBJECT ............................................................................................................ 46 
16.0 SAFETY MONITORING AND REPORTING ............................................................................... 47 
16.1 Adverse Events ............................................................................................................................ 47 
16.1.1. Reporting of AEs ......................................................................................................................... 47 
16.2 Serious Adverse Events ............................................................................................................... 48 
16.2.1 Serious Adverse Event Reporting ................................................................................................. 48 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Reporting of SAEs ................................................................................................................................... 50 
16.2.2   Protocol Specific Exceptions to Serious Adverse Event Reporting ........................................... 51 
16.3 Safety Oversight Committee (SOC) ............................................................................................ 51 
17.0 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................... 52 
17.1 Monitoring ................................................................................................................................... 52 
17.2 Audits ........................................................................................................................................... 52 
18 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ........................................................... 53 
18.1 Regulatory and Ethical Compliance ............................................................................................ 53 
18.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee .................................. 53 
18.3 Informed Consent ......................................................................................................................... 53 
18.4 Data and Safety Monitoring ......................................................................................................... 54 
18.5 Protocol Amendments .................................................................................................................. 54 
18.6 Publication Plan ........................................................................................................................... 54 
19 Privacy, Confidentiality, and Data Storage......................................................................................... 55 
20 Data Collection and Maintenance ....................................................................................................... 55 
20.1 Study Documentation ................................................................................................................ 55 
20.2 Case Report Forms (CRFs) .......................................................................................................... 56 
20.3 Data Management Procedures and Data Verification .................................................................. 57 
21 Study Closure ...................................................................................................................................... 57 
21.1 Records Retention ........................................................................................................................ 57 
22 STATISTICAL METHODS AND DATA ANALYSIS .................................................................... 58 
22.1 Analysis Sets ................................................................................................................................ 58 
22.2 Patient Demographics and Other Baseline Characteristics .......................................................... 58 
22.3 Study Treatments ......................................................................................................................... 58 
22.4 Primary Objective ........................................................................................................................ 58 
22.4.1 Variable ......................................................................................................................................... 58 
22.4.2 Statistical Hypothesis, Model, and Method of Analysis ............................................................... 58 
22.4.3 Handling of missing values, censoring, and discontinuations ...................................................... 59 
22.5 Secondary Objectives................................................................................................................... 59 
22.5.1 Key Secondary Objectives ............................................................................................................ 60 
22.5.2 Exploratory Objectives ................................................................................................................. 60 
22.5.3 Statistical Analysis for Secondary Objectives .............................................................................. 60 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
22.6 Interim Analysis ........................................................................................................................... 60 
22.7 Accrual and Follow-Up ................................................................................................................ 61 
23 REFERENCES ................................................................................................................................... 62 
24 LIST OF APPENDICES ..................................................................................................................... 64 
24.1 APPENDIX 1: Performance Status Criteria: ECOG ................................................................... 65 
24.2 APPENDIX 2: Information on Possible Drug Interactions Osimertinib ..................................... 66 
24.3 APPENDIX 3: Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law ............................................................................................................ 68 
24.4 APPENDIX 4: Measure of Effect ................................................................................................ 72 
25.5  APPENDIX 5: Standard Cockcroft and Gault Formula for Calculated Creatinine 
Clearance .............................................................................................................................................. 79 
 
 
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
AUC 
Area Under the Curve 
BIRC 
Blinded Independent Central Review 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMax 
Peak Concentration 
CMin 
Trough Concentration 
CR  
Complete Response 
CRF 
Case Report Form (sometimes referred to as Clinical Report Form). A printed or electronic 
form for recording study participants’ data during a clinical study, as required by the 
protocol. 
CMP 
Comprehensive Metabolic Panel 
CRT 
Chemotherapy-Radiation Therapy 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events; National Cancer Institute, Version 4.0 
CYP34A 
Cytochrome P450 3A4 
CTQA 
Clinical Trials Quality Assurance 
DCI 
Duke Cancer Institute 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interaction 
DLT 
Dose Limiting Toxicity 
 
DOR 
Duration of Response 
DSMB 
Data and Safety Monitoring Board 
DUHS/DUMC 
Duke University Health System/Duke University Medical Center 
ECOG  
Eastern Cooperative Oncology Group  
EGFR 
Epidermal Growth Factor Receptor 
 
FDA 
Food and Drug Administration 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
ILD 
Interstitial Lung Disease 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
IRB 
Institutional Review Board 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PI 
Principal Investigator 
PK  
Pharmacokinetic 
p.o. 
per os/by mouth/orally 
 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
PS 
Performance status 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SOC 
Safety Oversight Committee 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
Upper Limit of Normal 
 
WBC 
White Blood Cells 
 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Histologically confirmed Stage 4 
NSCLC 
2. TKI Treatment naive 
3. EGFR mutation testing by CLIA 
certified laboratory with exon 18 G719X, 
exon 20 S768I, or exon 21 L861Q 
4. PS of 0-1  
5. Adequate organ function 
6. Ejection fraction ≥ 45% 
7. Measurable Disease per RECIST 1.1 
Osimertinib until disease progression, 
unacceptable toxicity or withdraw of 
consent  

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
1.0 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
 
1.1 
Protocol Synopsis  
 
This is a single arm phase 2 study to investigate the activity of osimertinib in patients with stage 
4 non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation 
exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients will be epidermal growth factor 
receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment naïve.  The study will use RECIST 
1.1 for assessment of efficacy and Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. 1 
 
Primary Objective: Objective response rate (ORR) as assessed by investigator using 
RECIST 1.1 
 
Secondary Objectives: 
1. Progression free survival (PFS) using RECIST as assessed by the investigator 
2. Safety 
3. Overall survival (OS) 
 
      Exploratory objectives:   
1. Estimate the response rate and PFS in the specific mutation subsets of exon 18 G719X, 
exon 20 S7681, exon 21 L861Q or compound mutations  
 
Hypotheses: Osimertinib has demonstrated activity in patients with EGFR exon 19 or exon 21 
L858R mutations, and with the resistance mutation exon 20 T790M and is currently approved by 
the United Sates Food and Drug Administration for this patient population. There no approved 
targeted therapies for patients with EGFR mutations of exon 18 G719X, exon 20 S7681, or exon 
21 L861Q. This study will investigate the activity of osimertinib in patients with these EGFR 
mutations to determine if a larger prospective clinical trial should be pursued. 
 
1.2 
Research Summary 
 
 
For patients with advanced NSCLC which harbor activating EGFR exon 19 deletion and exon 21 
L858R mutations first-line therapy with EGFR tyrosine kinase inhibitor (TKI) (e.g. erlotinib, 
gefitinib, or afatinib) is the standard first-line therapy.2-5  EGFR exon 19 deletion and exon 21 
L858R mutations are the majority of EGFR mutations.6,7  The United States Food and Drug 
Administration (FDA) approval for epidermal tyrosine kinase inhibitors is restricted to these 
specific mutations. In addition to these exquisitely sensitive mutations, there are other EGFR 
mutations identified present in 4% of NSCLC with adenocarcinoma. Several of the less common 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
EGFR mutations have demonstrated sensitivity to EGFR TKI such as exon 18 G719A, G719C, 
and G719S (approximately 6% of EGFR mutations), exon 20 S768I (approximately 1.5% of 
EGFR mutations) and exon 21 L861Q (approximately 3% of EGFR mutations).8 EGFR TKIs have 
demonstrated activity in patients with uncommon EGFR mutations (defined as exon 18 G719X, 
exon 20 S768I, or exon 21 L861Q) but the ORR and PFS are lower. A subset analysis of phase 3 
trials demonstrated activity of afatinib demonstrated activity, but 40% of patient required dose 
reduction related EGFR-associated adverse events.9,10 The standard first-line therapies for 
patients with NSCLC which harbor these mutations is pembrolizumab alone or in combination 
with chemotherapy, and at the time of disease progression is single agent chemotherapy or single 
agent immunotherapy.11-15 There is not a targeted therapy approved for this patient population.  
 
For patients with an EGFR exon 19 or exon 21 L858R mutation who have progressed on first-
line EGFR TKI and have an exon 20 T790M mutation osimertinib is the standard and the FDA 
approved therapy.16-18  Osimertinib retains the activity against the activating EGFR mutation, 
with activity against the resistance T790M resistance mutation, and less EGFR associated 
adverse events since there is relative sparing of the EGFR wild-type receptor. The FDA 
approved dose of osimertinib is 80 mg daily.  
 
This single arm study will investigate the activity of osimertinib in patients with EGFR exon 18 
G719X, exon 20 S768I, or exon 21 L861Q mutations to determine if it has sufficient activity and 
an acceptable safety profile for further investigation.  
 
2.0 BACKGROUND AND SIGNIFICANCE 
2.1 
         Disease Background   
 
The rate of epidermal growth factor (EGFR) mutations in non-small cell lung cancer (NSCLC) 
with adenocarcinoma histology is approximately 15%.6,7 For patients with NSCLC with EGFR 
exon 19 deletion and exon 21 L858R point mutations first-line therapy with a  EGFR tyrosine 
kinase inhibitor (TKI) (e.g. gefitinib, erlotinib or afatinib) is the standard of care. The current 
FDA approval for these three agents is specifically for these activating mutations. EGFR TKI 
activity in EGFR mutant NSCLC with these activating mutations is due to the increased binding 
of the TKI compared to the binding of ATP leading to inhibition of the EGFR pathway and 
upregulation of pro-apoptotic pathway.19 
 
In addition to these exquisitely sensitive mutations, there are other EGFR mutations identified 
present in 4% of NSCLC with adenocarcinoma.20 Several of the uncommon mutations have 
demonstrated sensitivity to EGFR TKI such as exon 18 G719A, G719C, and G719S 
(approximately 6% of EGFR mutations), exon 20 S768I (approximately 1.5% of EGFR 
mutations) and exon 21 L861Q (approximately 3% of EGFR mutations).8 These mutations have 
activation of the EGFR pathway without the increased affinity for the EGFR TKI observed in the 
EGFR exon 19 deletion and exon 21 L858R mutation.19  The inhibitory concentration of first 
generation EGFR TKI required is higher in these mutations compared to EGFR exon 19 deletion, 

 
 
12 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
and the response rate to first generation reversible EGFR TKIs rarely exceed 55%.8  Patients 
with uncommon EGFR mutations were enrolled in two phase 3 trials of afatinib, an irreversible 
EGFR TKI, compared to platinum-based chemotherapy.4,5  In a retrospective analysis of the two 
phase 3 trials, afatinib is associated with a response rate of greater 55%, especially in NSCLC 
EGFR mutations G719X, L861Q, and S768I.4,5,9  However, the subset of patients with G719X, 
L861Q and S768I EGFR mutations were 18 patients, 16 patients, and 8 patients, respectively. 
This study reveals activity of EGFR TKI’s in patients with these mutations. However, 
approximately 40% of patients treated with afatinib 40 mg daily require a dose reduction, largely 
related to EGFR-related adverse events, which raises concerns about the tolerability of this 
agent.10    A post-hoc analysis of the patients assigned to afatinib in two phase 3 trials did not 
reveal a difference in progression-free survival (PFS) between patients who underwent dose 
reduction in the first 6 months and those who did not.21 However, patients with uncommon 
mutations represent a small subset of patients (approximately 10% of patients, n=52), and 
efficacy data are not available from this subset.  
 
The fundamental problems with assessment of EGFR TKI activity in this uncommon mutation 
subtypes has been that most of the data are retrospective and consisted of small subsets.22 The 
definition of “uncommon” mutation has varied from study to study which further complicates the 
assessment of the efficacy. There is concern that the first generation EGFR TKIs (gefitinib, 
erlotinib) do not achieve the necessary inhibitory concentration, and afatinib has issues with 
tolerability and the frequent need for dose reduction. Collectively these mutations represent a 
significant proportion the EGFR mutant patient population. 
 
Current therapy  
 
The current standard first-line therapy is a platinum doublet for patients with stage 4 disease and 
uncommon EGFR mutations. Platinum and pemetrexed has an objective response rate (ORR) of 
approximately 30% and a median PFS 4 to 5 months in patients with an EGFR mutation.18,23  
The standard second-line therapies are immunotherapy and docetaxel. A response rate of 
approximately 5-10% and median PFS of approximately 3 months are observed with docetaxel, 
and with immunotherapy a response rate of 20% is observed in the intent-to-treat patient 
population. The response rate is estimated to be lower in the EGFR mutant patient population.13-
15,24  In subset analyses of phase 3 trials of immunotherapy compared to docetaxel a survival 
benefit was not observed with immunotherapy in the EGFR mutation subset.13-15A higher 
mutational burden and a history of smoking is associated with benefit from immunotherapy, and  
patients with EGFR mutant NSCLC  have lower mutational burden and frequently a history of 
never smoking or light smoking.25  These clinical and biomarker data have raised questions 
about the activity of immunotherapy in patients with EGFR mutant NSCLC. 
 
Recently the second and third-line approval of erlotinib was rescinded by the FDA. Afatinib is 
approved in the second-line setting only for squamous histology NSCLC. This limits the 
availability of EGFR TKIs in the second-line setting for patients with EGFR mutations besides 
the exon 19 deletions and exon 21 L858R mutation. Thus, there are limited effective options for 
patients with uncommon EGFR mutations. 

 
 
13 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
 
2.2 
        Study Agent 
 
The T790M gatekeeper resistance mutation is located in the hinge region of the ATP-binding 
pocket of the EGFR kinase domain where the bulky methionine side chain prevents binding of 
first-line EGFR TKI.26 In contrast to first-generation inhibitors, osimertinib (AZD9291, 
TAGRISSO) is a potent irreversible inhibitor of both the single EGFR mutant (TKI-sensitivity-
conferring mutations) and dual EGFR mutant/T790M (TKI resistance-conferring mutation) 
forms of EGFR. As a result, osimertinib has the potential to provide clinical benefit to patients 
with advanced NSCLC harboring both the single sensitivity mutations and the T790M resistance 
mutation following prior therapy with an EGFR TKI.  
 
In vitro studies have shown osimertinib (AZD9291, Tagrisso) to be a potent and selective 
irreversible inhibitor of isolated wild-type and mutant EGFRs (IC50s <10 nm). Cell line EGFR 
phosphorylation assays demonstrated potent inhibition of single-activated (EGFR mutant) and 
double-T790M mutant (EGFR mutant/T790M) assays, with much weaker inhibition towards 
wild-type EGFR. In vitro washout and time-dependent cellular kinetic studies demonstrated an 
irreversible mechanism of action of osimertinib. Oral treatment of mice bearing EGFR mutant 
and EGFR mutant/T790M exograft tumors leads to profound tumor growth regression. In 
contrast, higher doses of osimertinib were required to achieve significant tumor growth 
inhibition in wild-type EGFR xenograft models. Xenograft growth regression with osimertinib 
was accompanied by dose-and time-dependent pharmacodynamic inhibition of phospho-EGFR 
and the key downstream biomarkers phospho-AKt and phospho-ERK across mutant and wild-
type EGFR disease models in vivo. Furthermore, chronic longer term oral treatment with 
osimertinib led to complete and sustained macroscopic disappearance of an EGFR mutant 
xenograft tumor. In support of this hypothesis, the EGFR mutant cell line showed greater time to 
resistance in response to the osimertinib treatment in vitro compared to earlier generation EGFR 
inhibitors. The active metabolites of AZD9291, AZD5104 and AZ7550, showed similar 
pharmacological selectivity and activity profiles to parent, although AZ5104 showed a smaller 
margin of selectivity against wild-type EGFR in vitro.  
 
2.3 
 Preclinical and Clinical Trial Data 
 
Non-clinical pharmacology 
 
Non-clinical in vitro studies have demonstrated potent inhibition of mutant EGFR activity in 
biochemical enzyme assays and across NSCLC cell lines harbouring clinically relevant EGFR 
mutations (T790M, L858R and exon 19 deletion), with lower activity against wild-type EGFR. 
Moreover, osimertinib has caused profound tumour regression across representative mutant 
EGFR xenograft and transgenic disease models in vivo at clinically relevant concentrations, 
which was accompanied by dose and time dependent pharmacodynamic target effects. 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
Taken together, in vitro and in vivo non-clinical studies have provided strong support that 
osimertinib is more potent towards mutant EGFR compared with wild-type EGFR. 
 
Osimertinib has two active metabolites, AZ5104 and AZ7550. The geometric mean exposure 
area under the plasma concentration time curve (AUC) of each metabolite (AZ5104 and 
AZ7550) was approximately 10% of the exposure of osimertinib at steady-state. AZ7550 
displays near identical pharmacology properties in vitro to osimertinib. In contrast, AZ5104 has 
greater potency against mutant and wild-type EGFR in vitro than osimertinib, which suggests 
this metabolite may have a smaller selectivity margin compared with mutant EGFR than 
osimertinib. 
 
Osimertinib is a highly selective inhibitor of mutant EGFR, showing minimal off-target kinase 
activity when tested in a broad biochemical kinome panel, only showing significant potency 
against 18 other kinases (including ACK1, BLK, ErbB2, ErbB4, BRK, MLK1, MNK2), although 
the clinical significance of this biochemical activity remains unclear. 
 
Osimertinib, AZ5104 and AZ7550 inhibited the hERG-encoded potassium channel with IC50 
values of 0.69 μM, 17.48 μM and >33 μM, respectively. 
 
There were no notable effects on the respiratory, visual, central nervous or cardiovascular 
systems in safety pharmacology studies. Reductions in gastric emptying and small intestinal 
transit were observed in rats. 
 
Pharmacokinetics and drug metabolism in animals 
 
Osimertinib is a moderately permeable compound in Caco-2 cells and has good absorption 
properties in rats and dogs. Osimertinib plasma protein binding is high (>94%) across mouse, rat, 
dog, monkey and in human plasma (94.7%). [14C]Osimertinib related material was shown to 
distribute to all tissues in a rat quantitative whole-body autoradiography (QWBA) study and 
there was also evidence that [11C]osimertinib and its active metabolite [11C]AZ5104 penetrated 
the blood-brain barrier (BBB) in a cynomolgus monkey PET study. In mouse, rat, dog and 
human hepatocytes, osimertinib metabolism was primarily to hydroxylated and dealkylated 
products with conjugation to a range of glutathione, cysteineglycine, glucuronide and sulphate 
conjugates with all human metabolites also produced by rat and dog hepatocytes. 
 
The major route of osimertinib excretion in rats and dogs was via the feces with only minor 
elimination observed in urine. In vitro data supports CYP3A4/5 as the major enzyme responsible 
for the metabolism of osimertinib and its two active metabolites AZ5104 and AZ7550. These 
data led to the conduct of clinical drug-drug interaction (DDI) studies with itraconazole (strong 
CYP3A4 inhibitor) and rifampicin (strong CYP3A4 inducer). In vitro, osimertinib showed 
potential to inhibit intestinal breast cancer resistance protein (BCRP) and CYP3A4 that led to the 
conduct of clinical DDI studies with rosuvastatin (BCRP substrate) and simvastatin (CYP3A4 
substrate). 

 
 
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Toxicology 
 
The principal histopathological findings following daily oral dosing of osimertinib in rats and 
dogs were consistent with inhibition of wild-type EGFR. In a rat female fertility study 
osimertinib was associated with a reversible increase in post-implantation loss. Osimertinib had 
marked adverse effects on embryonic survival plus early postnatal viability and growth when 
administered to pregnant or lactating rats. Osimertinib has shown no genotoxic or phototoxic 
potential. The integrated non-clinical safety data supports the continued clinical development of 
osimertinib in the patient populations studied in the ongoing clinical studies. 
 
Clinical data 
At the data cut-off date (DCO) of 12 November 2016, 2777 subjects have been exposed to study 
treatment (osimertinib alone, osimertinib in combination with another treatment, or comparator) 
in AstraZeneca-sponsored clinical studies. Of these, 2141 NSCLC patients and 118 healthy 
volunteers have been exposed to osimertinib (osimertinib alone [2080] or osimertinib in 
combination with another treatment [179]) in the ongoing osimertinib AstraZeneca-sponsored 
clinical program, and an additional 4188 NSCLC patients have participated in the osimertinib 
Expanded Access Program. The key findings from the clinical program to date are summarized 
below. 
 
Clinical pharmacokinetics 
Osimertinib pharmacokinetic parameters have been characterized in healthy subjects and 
NSCLC patients. Based on population pharmacokinetic analysis, osimertinib apparent plasma 
clearance is 14.2 L/h, apparent volume of distribution is 997 L and terminal half-life is 
approximately 48 hours. The area under the plasma concentration-time curve (AUC) and 
maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 mg 
to 240 mg dose range (i.e, 0.25 to 3 times the recommended dosage) after oral administration and 
exhibited linear pharmacokinetics (PK). Administration of osimertinib orally once daily resulted 
in approximately 3-fold accumulation with steady state exposures achieved after15 days of 
dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold. 
The median time to Cmax of osimertinib was 6 hours (range 3 to 24 hours). The absolute 
bioavailability of TAGRISSO is 70% (90% CI 67, 73). Neither food nor gastric pH affects the 
exposure of osimertinib. 

 
 
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In vitro, plasma protein binding of osimertinib is 94.7% (5.3% free). Osimertinib has also been 
demonstrated to bind covalently to rat and human plasma proteins, human serum albumin and rat 
and human hepatocytes. 
In vitro studies indicate that osimertinib is metabolized predominantly by CYP3A4/5. Two 
pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma 
after oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and 
AZ7550) was approximately 10% of the exposure of osimertinib at steady-state. 
Osimertinib is primarily eliminated in the feces (67.8%) and to a lesser extent in the urine 
(14.2%).  Unchanged osimertinib accounted for approximately 2% of the elimination. 
Based on in vitro studies, osimertinib is a competitive inhibitor of CYP 3A4/5 but not CYP1A2, 
2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinically relevant concentrations. 
In vitro, osimertinib is not a substrate of OATP1B1 and OATP1B3 and does not inhibit P-gp, 
OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MATE1 and MATE2K at clinically relevant 
concentrations. Based on in vitro studies, osimertinib is a substrate of P-glycoprotein and BCRP, 
but is unlikely to result in clinically relevant drug interactions  
Based on clinical DDI studies, interactions with strong CYP3A4 inhibitors are unlikely but 
strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may also 
increase the exposure of co-administered BCRP substrates. Clinical PK interactions with co-
administered CYP3A4 substrates are unlikely. 
No clinically significant differences in the pharmacokinetics of osimertinib were observed based 
on age, sex, ethnicity, body weight, smoking status, mild or moderate or severe renal impairment 
(creatinine clearance [CLcr] >15 mL/min by Cockcroft-Gault) or mild or moderate hepatic 
impairment (mild: total bilirubin less than or equal to the upper limit of normal [ULN] and 
aspartate aminotransferase [AST] greater than ULN or total bilirubin between 1 to 1.5 times 
ULN and any AST; moderate: total bilirubin between 1.5 to 3 times ULN and any AST). As 
patients with CLcr less than 15 mL/min, patients on dialysis, or patients with severe hepatic 
dysfunction were not included in the clinical trials, the appropriate dose of osimertinib has not 
been established in these patients. 
Based on an analysis of dose-exposure response relationships over the dose range of 20 mg (0.25 
times the recommended dose) to 240 mg (3 times the recommended dose), no apparent 
relationship between osimertinib exposure and objective response rate, duration of response and 
progression-free survival was identified. Over the same dose range, increased exposure led to 
increased probability of adverse reactions, specifically rash, diarrhea and interstitial lung disease 
(ILD). A pharmacokinetic/pharmacodynamic analysis in AURA2 suggested a concentration-
dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% confidence 
interval [CI]: 16 msec) at a dose of 80 mg orally (PO). 

 
 
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In summary, the clinical pharmacology package provides characterization of the key PK and 
ADME characteristics of osimertinib and provides confirmatory data in support of the 80 mg 
dose and adequate labelling for special populations. From a clinical PK perspective, these data 
support a once daily fixed 80 mg PO dose for this advanced NSCLC population. 
Renal Impairment 
A formal clinical study to investigate the impact of severe renal impairment on osimertinib PK is 
planned. In Study 11 (14C-ADME) osimertinib, AZ5104 and AZ7550 were shown to undergo 
negligible renal clearance; however, as renal impairment can adversely affect some pathways of 
hepatic / gut metabolism, the impact of renal impairment was assessed in the population PK 
analysis. 
In the population PK analysis, there was no impact of creatinine clearance on the PK of 
osimertinib (N=1086, median (min-max) baseline creatinine clearance of 82 [20.5 to 196] 
mL/min). Based on a population pharmacokinetic analysis of 471 patients with mild renal 
impairment (CLcr 60 to <90 mL/min), 208 patients with moderate renal impairment (CLcr 30 to 
<60 mL/min), 5 patients with severe renal impairment (CLcr 15 to <30 mL/min) and 402 
patients with normal renal function (≥90 mL/min), osimertinib apparent clearance (and exposure) 
were similar. Osimertinib can be administered to patients with mild, moderate and severe renal 
impairment (CLcr ≥15 mL/min) without any dose adjustments. Caution should be exercised 
when treating patients with end stage renal impairment (CLcr <15 mL/min) 
Hepatic impairment 
In Study 11, osimertinib was shown to undergo significant metabolism mediated clearance 
presumably with the liver as a major site of biotransformation and hence, hepatic impairment 
might be expected to lead to increased exposure of osimertinib 
A clinical study investigating the impact of mild and moderate hepatic impairment (as assessed 
by Child-Pugh criteria) on osimertinib pharmacokinetics is ongoing (Study 08). In AURA Phase 
I, AURA extension and AURA2 patients were excluded if they had: 
• ALT >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the 
presence of liver metastases 
• AST >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the 
presence of liver metastases 
• Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of 
documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver metastases 
No clinical studies have been conducted to specifically evaluate the effect of hepatic impairment 
on the pharmacokinetics of osimertinib. Population PK analysis of 104 patients with mild hepatic 
impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin between 1.0 to 1.5 times 
ULN and any AST), 8 patients with moderate hepatic impairment (total bilirubin between 1.5 

 
 
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times to 3.0 times ULN and any AST) and 972 patients with normal hepatic function (total 
bilirubin ≤ULN and AST ≤ULN), osimertinib apparent clearance (and exposures) were similar. 
Hence, no dose adjustment is necessary for mild or moderate hepatic impairment. Due to no 
patients with severe hepatic dysfunction being evaluated in the clinical trials, dose 
recommendation is not available for subjects with severely impaired hepatic function. 
Food 
The impact of food on the bioavailability of osimertinib was evaluated in NSCLC patients in a 
definitive study (Study 09) at the 80 mg dose with the film-coated tablet (the proposed 
commercial formulation).  The geometric least square (LS) mean ratios comparing fed to fasted 
treatments for osimertinib Cmax  and AUC0–72  were 92.75% (81.40, 105.68) and 106.05% 
(94.82, 118.60), respectively and were contained within the predefined equivalence limits of 
70% to 143%.  Administration of the tablet with a high-fat meal did not affect median 
osimertinib tmax when compared with fasted conditions. 
An exploratory earlier assessment of the impact of food was also conducted in healthy volunteers 
in Study 05 (Part B) at 20 mg dose using the Phase 1 tablet formulation. Although this study was 
not powered to meet the criteria of a formal food effect study and used a fixed-sequence, 2-
period design, point estimates and 90% CIs of the ratios comparing fed to fasted treatments for 
osimertinib Cmax and AUC were also contained within the limits of 70% to 143. 
Based on the results from the definitive food effect study (Study 09) and supporting results from 
the exploratory study (Study 05, Part B) it is recommended that osimertinib can be taken with or 
without food.  
 
Clinical efficacy 
First-line locally advanced or metastatic NSCLC patient population 
In first-line (treatment-naïve) NSCLC patients, a total of 60 patients received PO treatment with 
osimertinib in the AURA Phase I study (30 patients each at 80 mg and 160 mg respectively). The 
overall ORR was 77% (95% CI: 64, 87) and the overall disease control rate (DCR) was 98% 
(95% CI: 89, 100). The median PFS was 19.3 months, with maximum duration of response 
(DoR) at 22.1 months. The percentage of patients remaining progression-free at 12 months was 
72% (95% CI: 59, 82) and at 18 months 55% (95% CI: 41, 67). 
2nd line or greater, T790M mutation positive, advanced NSCLC patient population 
The AURA3 study demonstrated superior efficacy of osimertinib compared to chemotherapy in 
patients with advanced EGFR T790M mutation positive NSCLC, whose disease has progressed 
on or after EGFR TKI therapy: 

 
 
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• For the primary objective of progression free survival (PFS) by Investigator assessment, 
at 59.7% maturity, there was a statistically significant and clinically meaningful 
improvement in PFS for patients on osimertinib 80 mg PO once-daily vs. those on 
chemotherapy based on investigator assessment (hazard ratio [HR]: 0.30, 95% CI: 0.23, 
0.41; p-value: <0.001), indicating a 70% reduction in risk of disease progression or death 
(in the absence of a Response Evaluation Criteria In Solid Tumours [RECIST] 
progression) in the osimertinib arm. Treatment with osimertinib resulted in a 5.7-month 
improvement in median PFS compared to chemotherapy (10.1 months [95% CI: 8.3, 
12.3] vs. 4.4 months [95% CI: 4.2, 5.6]). 
The superiority of osimertinib over chemotherapy for PFS was independent of 
chemotherapy regimen used in the study, and was maintained across all predefined 
demographic or disease subgroups. 
The median PFS by Blinded Independent Central Review (BICR) assessment was 11.0 
months (95% CI: 9.4, not calculable [NC]) in the osimertinib arm and 4.2 months (95% 
CI: 4.1, 5.6) in the chemotherapy arm, (HR: 0.28, 95% CI: 0.20, 0.38; p<0.001). 
• The objective response rate (ORR; unadjusted) by investigator assessment was 70.6% 
(95% CI: 64.9, 75.9) in the osimertinib arm vs. 31.4% (95% CI: 23.9, 39.8) in the 
chemotherapy arm. There was a clinically meaningful and statistically significant 
improvement in ORR in the osimertinib arm compared with the chemotherapy arm, with 
an odds ratio (OR) of 5.39 (95% CI: 3.47, 8.48) (p-value: <0.001). 
 
• The median DoR (51.9% maturity) based on the investigator assessment was 9.7 months 
(95% CI: 8.3, 11.6) in the osimertinib arm vs. 4.1 months (95% CI: 3.0, 5.6) in the 
chemotherapy arm. There was a statistically significant improvement in expected DoR 
(EDoR) for patients on osimertinib compared with those on chemotherapy (ratio of 
EDoR: 6.22; 95% CI: 4.04, 9.57; p-value: <0.001). 
 
• The analysis of overall survival (OS) was performed at 26.0% overall maturity. The HR 
of OS was 0.72 (99.96% CI: 0.34, 1.52). A numerical advantage in OS for patients on 
osimertinib compared to patients on chemotherapy was observed, which did not reach 
statistical significance (p-value 0.121). The median OS was not calculable in either arm, 
the lower limit of the 95% CI was 20.53 months in the osimertinib arm and 20.47 months 
in the chemotherapy arm 
 
• Analysis of patient-reported outcomes (PRO) findings demonstrated a statistically 
significant difference (p≤0.001) in mean change from baseline between osimertinib and 
chemotherapy during the overall time period from randomisation until 6 months, for all 5 
pre-specified key lung cancer symptoms (cough, dyspnoea, pain in chest, fatigue, and 
appetite loss); with prolonged time to deterioriation for dyspnea and cough. 
 

 
 
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Protocol TOP 1703 
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• The CNS metastases efficacy analysis results in AURA3 demonstrate the superior 
efficacy of osimertinib compared to chemotherapy in patients with CNS metastases. A 
BICR assessment of CNS efficacy in patients with CNS metastases at baseline showed a 
clinically meaningful improvement for patients randomised to receive osimertinib vs. 
chemotherapy. The improvements in CNS efficacy outcomes were consistent across 
multiple analyses (ORR of 70% vs 31.3%, OR of 5.13 with a p-value of 0.015; DoR 8.9 
months  vs 5.7 months; PFS 11.7 months vs 5.6 months, for osimertinib vs. 
chemotherapy, respectively). Efficacy findings in the osimertinib arm of the AURA3 
study were consistent with those in the pooled Phase II studies. The pooled single arm 
Phase II studies (AURA extension and AURA2) support the consistency and durability of 
effect of osimertinib 80 mg PO once-daily in a broader population of patients (including 
second [2nd] line and ≥third [3rd] line therapy) with advanced EGFR T790M mutation 
positive NSCLC with longer follow up. 
 
• The pooled confirmed ORR in the evaluable-for-response analysis set based on blinded 
independent central review (BICR; primary analysis) was 66.0% (95% CI: 61.1, 70.7). 
 
• The durability of response was confirmed with a longer follow-up: the BICR assessed 
median DoR for the pooled analysis (44.3% maturity) was 12.5 months (95% CI: 11.1, 
NC). Based on a KM analysis, the estimated percentage of patients remaining in response 
at 9 months was 65.0% (95% CI: 58.5, 70.6) and 52.9% (95% CI: 45.9, 59.4) at 12 
months. 
 
• The median PFS in the full analysis set (FAS) was 11.0 months (95% CI: 9.6, 12.4) based 
on BICR assessment. 
 
• The median follow-up for OS was 13.4 months, however OS data were still immature. 
The median OS and upper limit were not calculable but the lower limit was 16.4 months 
 
• Overall, the efficacy variables determined by both BICR and investigator assessment 
showed similar results. 
 
• A BICR assessment of CNS efficacy in a subgroup of patients with CNS metastases from 
the pooled Phase II studies showed consistent results with the AURA3 analysis. ORR in 
patients was 54.0% (95% CI: 39.32, 68.19); 80.4% of patients remained in response at 6 
months and 75.4% at 9 months. The Kaplan-Meier (KM) estimated percentage of patients 
alive and CNS progression-free at 6 and 12 months was 72.1% (95% CI: 56.8, 82.8) and 
56.3% (95% CI: 39.9, 69.9), respectively. 
 
In summary, the Phase III AURA3 study demonstrated clear evidence of overall favorable 
efficacy of osimertinib compared with the standard of care, chemotherapy. The CNS metastases 
efficacy analysis results in AURA3 also demonstrated the superior efficacy of osimertinib 
compared to chemotherapy in patients with CNS metastases. The overall efficacy and CNS 

 
 
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efficacy findings from the pooled single arm Phase II studies support the consistency and 
durability of effect of osimertinib in a broader population of patients (including 2nd-line and 
≥3rd-line therapy) with advanced EGFR T790M mutation-positive NSCLC with longer follow-
up and are consistent with the efficacy observed with osimertinib in AURA3 
2.4 Clinical safety and Rationale for Dose Selection, Regimen, and Treatment 
Duration 
Osimertinib 80 mg PO once-daily dose, approved by the FDA, has an acceptable safety profile 
for the intended advanced NSCLC population.  The standard clinical practice is to continue 
targeted therapies until disease progression or unacceptable toxicity.  
In the AURA3 study:  
The overall incidence of all causality AEs was 97.8% for the osimertinib arm and 99.3% for the 
chemotherapy arm. Regardless of causality, the majority of all adverse events (AEs) reported 
with osimertinib were mild or moderate in severity. Adverse events of Common Terminology 
Criteria for Adverse Events (CTCAE) Grade ≥3 were reported for a lower proportion of patients 
in the osimertinib arm than in the chemotherapy arm: 63 (22.6%) vs. 64 (47.1%) patients, with 
16 (5.7%) and 46 (33.8%)% of CTCAE Grade ≥3 considered related treatment by the 
investigator for osimertinib and chemotherapy respectively. A number of serious adverse events 
(SAEs) were reported for patients in the osimertinib arm than the chemotherapy arm: 50 [17.9%] 
vs. 35 [25.7%] patients. SAEs considered to be possibly related to study drug were less common 
in the osimertinib arm (8 [2.9%] patients) than the chemotherapy arm (17 [12.5%] patients) 
During the treatment period or 28-day follow-up period, death was due to disease under 
investigation plus a fatal AE in 0.7% of patients in each treatment arm; death due to a fatal AE 
only occurred in 0.7% osimertinib vs. no chemotherapy patients.  All other deaths were due to 
disease under investigation only. 
Osimertinib is well tolerated.  Adverse events leading to discontinuation (6.8% osimertinib arm 
vs 10.3% chemotherapy arm), dose reduction (2.9% osimertinib arm vs 12.5% pemetrexed, 
28.6% cisplatin, 10.6% carboplatin of the chemotherapy arm), or dose interruption/delay (12.9% 
osimertinib arm vs 20.6% pemetrexed, 11.9% cisplatin, and 16.0% carboplatin) were low and 
less common in the osimertinib arm than in the chemotherapy arm. 
The most commonly reported AEs (ie, >15%) in the osimertinib arm vs the chemotherapy arm, 
respectively were: diarrhea (40.5% vs. 11.0%), rash ([grouped terms] 33.7% vs. 5.9%), dry skin 
(18.6% vs. 4.4%), decreased appetite (17.9% vs. 36.0%), paronychia (16.5% vs. 1.5%), cough 
(16.5% vs.14.0%), nausea (16.1% vs. 49.3%), and fatigue (15.8% vs. 27.9%). 
In the osimertinib clinical program: 

 
 
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ILD or ILD-like adverse reactions (eg, pneumonitis) were reported in 3.5% and were fatal in 
0.6% (5 patients) of the 833 patients who received osimertinib in AURA studies (who received at 
least one dose of 80 mg in the 2nd-line or later setting).  The incidence of ILD was 8.2% in 
patients of Japanese ethnicity, 1.9% in patients of non-Japanese Asian ethnicity and 2.9% in non-
Asian patients.  The median time to onset of ILD or ILD-like adverse reactions was 2.7 months. 
Osimertinib leads to a predicted drug-related QTc interval prolongation at the 80 mg dose of 14.2 
msec with an upper bound (90% CI) of 15.8 msec, but with no evidence that this is associated 
with an increased risk of cardiac arrhythmias or Torsades de Point (TdP). In safety dataset of 833 
patients in AURA studies treated with osimertinib 80 mg, 0.7% (n=6) were found to have a QTc 
greater than 500 msec, and 2.9% (n=24) had an increase from baseline QTc greater than 60 
msec. 
Based on the available clinical trial data, a causal relationship between changes in cardiac 
contractility and osimertinib has not been established. 
Osimertinib has not been associated with gastrointestinal perforations or haemorrhagic diarrhoea 
and no events leading to dehydration or renal failure have been reported. No severe bullous, 
blistering or exfoliative skin conditions were observed. 
AstraZeneca considers there to be a reasonable possibility of a causal relationship between 
osimertinib, keratitis and related corneal disorders. 
Decreases from baseline in median values for platelets, neutrophils and leucocytes were 
observed early in treatment with osimertinib. Median values appear to stabilize after the initial 
drop with the majority of patients experiencing a single grade change or no change in CTCAE 
grade.  As would be expected with the small magnitude of these changes, no clinically 
significant sequelae in the population have been observed. 
Evaluation for potential liver toxicity has shown no apparent association of osimertinib with drug 
induced liver injury. In the Phase II studies approximately 5% of patients reported AEs of 
elevations in alanine aminotransferase (ALT) or AST and the vast majority of these elevations 
were Grade 1 or 2 changes. 
There is no apparent association of osimertinib with renal toxicity. 
Safety findings in the pooled single-arm Phase II studies were generally consistent with those 
observed in the osimertinib arm of AURA3. The most commonly reported AEs with osimertinib 
were low-grade gastrointestinal (GI) disturbances (primarily diarrhea) and skin effects (mainly 
rashes and acnes, paronychia, and dry skin). 
An increased incidence in the ILD reporting rate has been reported for the combination of 
durvalumab and osimertinib in Study D5160C00006 (the TATTON study). This study showed 
an incidence rate of 29.4% for pneumonitis/ILD-like events, at a data cut-off of 12 July 2016, 

 
 
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compared with an overall frequency of pneumonitis (including both non serious and serious 
cases) of around 2% for durvalumab monotherapy across all doses and indications and an overall 
frequency of pneumonitis/ILD of 2.4% for osimertinib monotherapy. 
In Phase I Clinical Pharmacology studies in healthy volunteers osimertinib was generally well 
tolerated without any significant safety concerns. The healthy volunteer dose limit is set to 80 mg 
as a single oral dose. Further details are provided in the osimertinib IB version 8. 
 
Clinical experience: Osimertinib Adverse Events 
 
Gastrointestinal tract effects  
 
Osimertinib can cause gastrointestinal tract side effects. Osimertinib has not been associated with 
gastrointestinal perforations or hemorrhagic diarrhea. No events leading to dehydration or renal 
failure have been reported. Investigators are advised to follow the general toxicity management 
guidelines regarding dose interruption and reduction as detailed in Section 9. 
 
Dermatological effects  
 
Osimertinib can cause dermatological side effects (diarrhea, rashes, acnes, paronychia and dry 
skin). No severe bullous, blistering or exfoliative skin conditions have been reported. 
Investigators are advised to follow the general toxicity management guidelines regarding dose 
interruption and reduction as detailed in Section 9.  
 
Ocular surface effects  
 
Keratitis and related corneal disorders have been reported with Osimertinib use. Investigators are 
advised to follow the general toxicity management guidelines regarding dose interruption and 
reduction as detailed in Section 9.  
 
 
Cardiovascular effects  
 
Osimertinib leads to a predicted drug-related QTc interval prolongation at the 80 mg dose, but 
with no evidence that this is associated with an increased risk of cardiac arrhythmias or Torsades 
de Point (TdP). Based on available clinical trial data, a causal relationship between effects on 
changes in cardiac contractility and osimertinib has not been established. Investigators are 
advised to follow the general toxicity management guidelines regarding dose interruption and 
reduction as detailed in Section 9. 
 
Respiratory effects  
 
ILD or ILD-like adverse reactions (eg, pneumonitis) have been reported in in patients who 
received Osimertinib who received at least one dose of 80mg in the 2nd line or later setting. An 

 
 
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increased incidence in the ILD reporting rate has been reported for the combination of 
durvalumab and osimertinb study (TATTON).  Investigators are advised to follow the general 
toxicity management guidelines regarding dose interruption and reduction as detailed in Section 
9. 
Liver effects  
 
In the Phase II studies, approximately 5% of patients reported AEs of elevations in alanine 
aminotransferase (ALT) or AST. The vast majority of these elevations were Grade 1 or 2 
changes. 
 
Hematopoietic effects  
 
Osimertinib is known to have hematopoietic side effects.  Decreases from baseline in median 
values for platelets, neutrophils and leukocytes were observed early in treatment with 
osimertinib.  Median values appear to stabilize after the initial drop with the majority of patients 
experiencing a single grade change or no change in the CTCAE grade. Investigators are advised 
to follow the general toxicity management guidelines regarding dose interruption and reduction 
as detailed in Section 9. 
 
Reproductive organ effects  
 
No reproductive toxicology or teratogenicity studies have been conducted with osimertinib to 
date, although the male and female reproductive tracts have been assessed as part of the 1-month 
toxicology studies.  
 
Renal effects  
 
There is no apparent association of osimertinib with renal toxicity. 
 
 

 
 
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3.0 STUDY RATIONALE 
3.1 
Trial Summary  
         
Abbreviated Title 
TOP 1703 
Trial Phase 
 II 
Clinical Indication 
Stage IV NSCLC ( TKI naïve with EGFR mutations: exon 18 G719X, 
exon 20 S7681 or exon 21 L861Q  
Trial Type 
Therapeutic treatment 
Type of control 
Open Label 
Route of administration 
Tablet(s) taken P.O. (by mouth) 
Trial Blinding 
Unblinded, open-label 
Study Treatment Group  
Single Arm   
Single daily dose of Osimertinib 80mg on days 1-28 of each study cycle. 
Number of trial subjects 
37 
Estimated enrollment period 
Approximately 3 years; first patient in First Quarter 2018. 
Estimated duration of trial 
Estimated at 5 years from the first patient in to last subject’s final 2 year 
follow-up 
Duration of Participation 
Active study treatment until progression or study treatment not tolerated 
followed for a maximum of 2 years after completion of study therapy.   
 
3.2 
 Design and Procedure  
 
This is an open label single arm phase 2 trial of osimertinib with the primary end-point of 
objective response rate (ORR) as assessed by the investigator, and uses Simon’s optimal 2-stage 
design. All patients will receive the FDA approved dose of osimertinib of 80 mg daily.   
 
3.3 
Selection of Subjects 
 
Patients with stage 4 non-small cell lung cancer who have undergone testing for EGFR mutations 
in a CLIA certified lab will be screened for study participation. Patients are required to 
demonstrate one of the following EGFR mutations: exon 18 G719X, exon 20 S7681 or exon 21 
L861Q. Additional details or the eligibility criteria are in section 5.0 
 
3.4 
Duration of Study 
 
At a rate of 1 to 2 patients per month, we expect that trial will take approximately 19~37 months 
to reach its target accrual if it will not be terminated earlier due to lack of efficacy according to 
the two-stage design. Patients will continue study therapy until disease progression, unacceptable 

 
 
26 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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toxicity or withdraw of consent. Patients who discontinue therapy for reasons other than disease 
progression will be followed for disease progression. After discontinuing study therapy patients 
will be followed for overall survival every 3 months by telephone or review of medical records 
until death or a maximum of 2 years from discontinuation of study therapy. 
  
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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4.0 OBJECTIVES AND ENDPOINTS 
 
Table 1 
 
 
Objective 
Endpoint 
Analysis 
Primary 
Objective response rate  
Patients experiencing a 
confirmed partial or complete 
response using RECIST 1.1 
(appendix 4) 
See Section 22 
Key 
Secondary 
Progression-free survival  Time from starting study 
therapy until disease 
progression using RECIST 1.1 
or death (whichever occurs 
first) (appendix 4) 
See Section 22 
Key 
Secondary 
Safety  
Common Terminology Criteria 
for Adverse Events (CTCAE) 
to assess adverse events  
See Section 22 
Key 
Secondary 
Overall survival  
Time from starting study 
therapy until death  
See Section 22 
Exploratory 
secondary 
ORR and PFS in the 
specific mutation subsets  
of exon 18 G719X, exon 
20 S7681, exon 21 
L861Q or compound 
mutations 
RECIST 1.1 (appendix 4)  
See section 22  
 
 
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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5.0 SUBJECT ELIGIBILITY 
 
The following guidelines are to assist physicians in selecting patients from whom protocol 
therapy is safe and appropriate.  Physicians should consider the risks and benefits of any therapy, 
and therefore only enroll patients for whom this study treatment is appropriate. For entry into the 
study, the following criteria MUST be met. 
 
5.1 Inclusion Criteria 
 
Patients are eligible to be included in the study only if they meet all of the following criteria.   
For time limits on imaging and blood tests please refer to on-study Tests and Procedures Table. 
 
1. EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR 
exon 18 G719X, exon 20 S768I, or exon 21 L861Q. Patients with compound (also 
referred to as multiple mutations) will be eligible provided the NSCLC demonstrates 
one of these mutations). 
2. Histological or cytological confirmation diagnosis of Stage 4 NSCLC per AJCC v7.  
3. Measurable disease by RECIST 1.1 (please refer to appendix 4)  
4. The following laboratory values obtained ≤ 14 days prior to study initiation. 
a. Hematology: ANC ≥ 1, 500 / ml, platelet count, ≥ 100,000 / ml, hemoglobin ≥ 9.0 
g / dl 
Hepatic:  
b. ALT or ALT  < 2.5 times ULN if no demonstrable liver metastases or <5 times 
ULN in the presence of liver metastases 
c. Total bilirubin < 1.5 times ULN if no liver metastases or < 3 times ULN in the 
presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) 
or liver metastases 
Renal: Cockcroft-Gault calculated creatinine clearance of ≥ 45 ml/min or creatinine 
≤1.5 x ULN 
5. Have normal QT interval on ECG evaluation QT corrected of ≤ 450 ms in males or ≤ 
470 ms in females obtained from 3 electrocardiograms (ECGs), using the screening 
clinic ECG machine-derived QTc value 
6. Cardiac ejection fraction of ≥ 45% 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1 
8. Negative pregnancy test done ≤7 days (or per institutional policy) prior to treatment, for 
women of childbearing potential only. Female must use highly effective contraceptive 
measures, and must have a negative pregnancy test or must have evidence of non-child-
bearing potential by fulfilling one of the following criteria at screening: 
a. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 
12 months following cessation of all exogenous hormonal treatments.  
b. Women under 50 years old would be considered postmenopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
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hormonal treatments and with LH and FSH levels in the post-menopausal range 
for the institution 
c. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation  
9. Male subjects must be willing to use barrier contraception 
10. Age ≥ 18 years 
11. Provision of written informed consent prior to any study-specific procedures 
 
5.2 Exclusion Criteria 
 
Patients will be excluded from the study if they meet any of the following criteria: 
 
1. Prior therapy with EGFR TKI therapy  
2. Greater than 2 lines of prior systemic therapy for metastatic non-small cell lung 
cancer.  
3. Any cytotoxic chemotherapy or other anticancer drugs from previous treatment 
regimen or clinical study within 14 days of first dose of study drug. 
4. Treatment with an investigational drug within 5 half-lives of the compound 
5. Other active malignancy ≤ 2 years prior to study enrollment.  EXCEPTIONS:  Non-
melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE:  If there is a history 
of prior malignancy, patients must not be receiving other specific treatment (i.e. 
hormonal therapy) for their cancer 
6. Prior radiotherapy ≤ 14 days 
7. Untreated symptomatic brain metastases (treated brain metastases are allowed 
provided > 14 days have elapsed from completion of radiotherapy and patient is 
neurologically stable as assessed by treating physician).  
8. Malabsorption syndrome, refractory nausea and vomiting, chronic gastrointestinal 
diseases, inability to swallow the formulated product or previous significant bowel 
resection that would preclude adequate absorption of osimertinib  
9. Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 
21 L858R mutation or exon 20 insertion. Patients with compound (also referred to as 
multiple mutations) will be excluded if the molecular testing includes one of these 
mutations 
10. Active pregnancy or breast-feeding: Pregnant women are excluded from this study 
because the effects of osimertinib on the development of the fetus are unknown, and 
there is potential for teratogenic or abortifacient effects.  Because there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with osimertinib, breastfeeding should be discontinued if the mother is treated 
with these agents. 
11. Grade ≥ 2 blurred vision, conjunctivitis, corneal ulcer, dry eye, or keratitis  
12. Men who intend to father children during the study or within 4 months afterward are 
excluded 
13. Major surgery within 4 weeks of first dose of study drug. 

 
 
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14. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time 
of starting study treatment, with the exception of alopecia or neuropathy 
15. Currently receiving (or unable to stop use prior to receiving the first dose of study 
treatment) medications or herbal supplements known to be potent inducers of 
CYP3A4 (at least 3 weeks prior) (Appendix 2).  
16. Significant medical history or unstable medical comorbidities, including but not 
limited to: 
a. Heart disease including congestive heart failure (NYHA Grade II or greater); 
unstable angina; prior myocardial infarction (NSTEMI or STEMI) within 6 
months prior to study enrollment; hypertension with a systolic blood pressure 
of >150 mm Hg or diastolic blood pressure of >100 mm Hg while on 
antihypertensive medication 
b. Any clinically significant abnormalities in rhythm, conduction or morphology 
of resting ECG e.g. complete left bundle branch block, third degree heart 
block and second degree heart block. 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age in first degree 
relatives or any concomitant medication known to prolong the QT interval 
d. Past medical history of interstitial lung disease, drug-induced interstitial lung 
disease, radiation pneumonitis which required steroid treatment, or any 
evidence of clinically active interstitial lung disease 
e. Any evidence of severe or uncontrolled systemic diseases, including 
uncontrolled hypertension and active bleeding diatheses 
f. Active infection or ongoing antiviral medication for viral infections including 
hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Screening 
for chronic conditions is not required. HIV-positive participants on 
combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with osimertinib. 
g. Ongoing use of warfarin (injectable low-molecular weight heparins are 
permitted). Patients must be off warfarin for > 7 days prior to enrollment 
 
5.2 Protocol Eligibility Waivers 
 
No waivers of inclusion or exclusion criteria will be granted.  All prospective patients must meet 
all entry criteria prior to enrollment in the study.  If there are any questions regarding the 
interpretation of an eligibility criterion for a potential patient, contact the principal investigator to 
discuss the potential patient to confirm eligibility. 
6.0 INCLUSION of WOMEN and MINORITIES 
 
There are no exclusions based on gender, race or ethnicity in this trial.  

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
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7.0 REGISTRATION PROCEDURE 
Patient registration for all patients signing informed consent will be completed through the Duke 
Cancer Institute (DCI) Clinical Research Unit (CRU) into EPIC and ONCORE systems within 1 
business day of obtaining consent.  Patients will be enrolled only after all pre-treatment 
evaluations are completed and all eligibility criteria are met.   
7.1 Registration for Outside Sites 
All patients signing informed consent at outside sites must be registered with Duke (including 
screen failures- indicate screen failure status on last page of eligibility checklist).  The following 
documents are to be completed by the investigator and/or designee and faxed to (919)-684-8926 
or scanned/emailed to the Thoracic Oncology Protocol Office (Thoracic-
multisite@dm.duke.edu):  All supporting documents should be sent de-identified. 
 
• TOP 1703 Eligibility Checklist with supporting source documents 
• Signed Informed Consent 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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8.0 STUDY PERIODS (Visit Requirements): 
 
The Schedule of Events (Table 4) summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
For the purpose of scheduling evaluations and to allow for patient and investigator schedules, 
holidays and weather or other emergencies requiring clinical facilities to be closed, a window of 
7 days will be applied to all study visits unless otherwise noted. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and or 
AstraZeneca for reasons related to subject safety. 
 
TABLE 4: Schedule of Events  
 
 
Assessment 
Screening1 
 
Days -28 to 0 
D1 of every 
Cycle1,2,13 
  
 
End of Study 
Treatment 
(EOT)3 
Follow-up 2,4,9 
Informed consent 
X 
 
 
 
Inclusion/exclusion Criteria 
X 
 
 
 
Demography Baseline 
Characteristics, Smoking Hx 
X 
 
 
 
Medical History5 
X 
X 
X 
 
Prior NSCLC therapies 
X 
 
 
 
Physical exam & vital signs5 
X 
X 
X 
 
Height 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
 
CBC with differential6 
X 
X 
X 
 
Serum Chemistries7 
X 
X 
X 
 
Serum pregnancy test8 
X 
X 
 
 
CT scan chest/abdomen9 
X 
X9 
 
 
Brain MRI9 
X 
X9 
 
 
Echocardiogram /MUGA12 
X 
 
 
 
EKG10 
 
X 
 
 
 
Tumor Histology 
X 
 
 
 
EGFR mutation status 
X 
 
 
 
Adverse event assessment 
X 
X 
X 
 
Study drug and diary11 
 
Provide & Review 
X 
 
Concomitant Meds 
X 
X 
X 
 
Subsequent Therapy and 
Survival Status 
 
 
 
X 
 
 
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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1Within 28 days prior to Day 1 of study therapy unless otherwise noted.  If screening (baseline) hematology 
and serum chemistries performed within 14 days of D1 of cycle 1, these do not need to be repeated.   
2 Unless otherwise noted, a window of 7 days will be applied to all study visits.  
3This visit should occur 30 days (+/- 3 days) after study therapy stops for whatever reason (adverse event, 
progression, or at discretion of the investigator). Patients who have an ongoing grade 4 AE or SAE at the 
time of discontinuation from study treatment will be contacted every 2 weeks until the event is resolved, 
determined to be irreversible by the investigator, or until the patient begins an alternate form of treatment. If 
patient is unable to make appointment due to health reasons (e.g. patient admitted to hospice) or the visit 
would place an undue burden on the patient in the assessment of the treating physician this visit may be 
omitted.  
4 Long-term follow up will occur every 3 months from the last administration of protocol-directed therapy 
for a maximum of 2 years or until death, whichever occurs first. Subsequent therapy and survival status will 
be documented. If molecular testing performed (e.g. molecular testing of tumor biopsy or circulating tumor 
DNA) the results of the testing will be recorded if available.  NOTE: follow-up may occur via phone or 
review of medical records, on-site visits are not required.    
5Complete history at baseline only, thereafter focused history on symptoms/adverse event. Patients will 
need baseline evaluation for unexplained eye symptoms to exclude corneal ulceration. Any eye symptoms 
on study should be referred for full ophthalmologic exam.  Vital sign assessment should include B/P, pulse 
temperature and oxygen saturation.  Weight will be taken at screening and Day 1 of every cycle. 
6This includes CBC with differential (auto or manual) and platelet count 
7Serum chemistries include blood urea nitrogen (BUN), creatinine, bilirubin, ALT (SGPT), AST (SGOT), 
alkaline phosphatase. Additional laboratory tests can be ordered if clinically indicated or at the discretion of 
the investigator but are not required by the protocol  
8Within 7 days of D1 (or institutional policy) of treatment with study therapy in women of childbearing 
potential 
9 CT scan chest and abdomen. MRI of the brain should be performed at baseline on all subjects and with 
every disease assessment in patients with known brain metastases to assess for intracranial disease 
progression. Patients without brain metastases will undergo repeat brain imaging as clinically indicated, and 
patients with brain metastases will undergo repeat imaging every 3 cycles starting with cycle 4 (i.e., cycle 4, 
7, 10, 13 etc). CT scan are done on day 1 of cycle 3, and then on cycles 5, 7, 9, 11, and 13 (every 2 cycles 
for the first year of study therapy), then every 3 cycles (i.e. 16, 19, 22) until disease progression. Patients 
who discontinue therapy for reasons other than disease progression will be followed for disease progression. 
The imaging schedule is at the discretion of the treating physician, but the recommended interval is every 6 
to 12 weeks.   Tumor imaging starting with D1 of cycle 5 may take place within 7 days prior to the study 
visit to accommodate holiday, weekends, and transportation issues.  
10 EKGs to be obtained in triplicate. EKGs consist of 12-lead studies performed within a 5 minute window 
after at least 10 minutes rest in supine position.  Repeat EKGs may be performed at the discretion of the 
investigator or per institutional standard. 
11 On C1D1 provide the patient medication diary for use.  D1 of all subsequent cycles patient diary is to be 
collected from previous cycle, reviewed with the patient, and a new diary provided. Collect at EOT if not 
returned earlier. 
12 Echocardiogram or MUGA scan to assess LVEF, testing to be repeated if clinically indicated based on 
assessment of the investigator or per institutional standard. 
13To be completed prior to dispensing next cycle.  
 
 

 
 
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8.1 Screening 
 
The following procedures and tests are to be performed within 28 days (unless otherwise 
specified) of study enrollment to confirm eligibility.  Baseline and Cycle 1 Day 1 procedures 
may be completed on the same day, however, screening assessments to confirm eligibility 
MUST have already been determined. Refer to Table 4 for details. 
 
1. Informed consent   
2. Review of past medical history and previous therapies for NSCLC    
3. Eligibility criteria review (Inclusion/exclusion) 
4. Demography/Baseline characteristics, smoking history 
5. A directed physical examination will be performed at the visit with vital signs 
including pulse, blood pressure, temperature, oxygen saturation, weight  
6. Height 
7. ECOG Performance status  
8. Routine blood work (CBC, chemistries) 
9. EKG in triplicate 
10. Echocardiogram/Muga  to assess LVEF  
11. Pregnancy test if applicable 
12. Tumor Histology 
13. EGFR mutation status 
14. Review of baseline sign/symptoms 
15. Review of concomitant medications  
16. Staging Disease assessment:  Brain MRI, CT scan of chest and abdomen 
 
8.2 On-Study Treatment Period:  Day 1 of each cycle or as noted in Table 4 
 
1. Review of interval medical history, concomitant medications and assessment of 
performance status 
2. A directed physical examination will be performed at the visit with vital signs 
including pulse, blood pressure, temperature, oxygen saturation, weight  
3. Laboratory: chemistry, and hematology  
4. A repeat ECG may be performed at the discretion of the investigator or per 
institutional standard. 
5. Echocardiogram/MUGA will be repeated if clinically indicated based on assessment 
of the investigator or per institutional standard   
6. MRI of the brain to be performed with every 3 cycles starting with cycle 4 (cycles 4, 
7, 10, 13 etc…) in patients with known brain metastases to assess for intracranial 
disease progression. Patients without brain metastases will undergo repeat brain 
imaging as clinically indicated.  
7. Adverse event assessment 
8. Review of study drug and diary  
9. Pregnancy test (if applicable)  

 
 
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10. CT Chest/abdomen are done on day 1 of cycle 3, and then on cycles 5, 7, 9, 11, and 
13 (every 2 cycles for the first year of study therapy). Then every 3 cycles (i.e. 16, 19, 
22).    
 
 
8.3 End of Study Treatment (30 days (+/- 3 days) after study therapy stops) 
 
1. Review of interval medical history since the last visit and assessment of performance 
status 
2. A directed physical examination will be performed at the visit with vital signs 
including pulse, blood pressure, temperature, oxygen saturation, weight 
3. Laboratory: chemistry and hematology 
 
8.4 Follow-up Period 
 
1. After discontinuing study therapy patients will be followed for overall survival every 
3 months by telephone or review of medical records until death or a maximum of 2 
years. Subsequent therapy and survival status will be documented. If molecular 
testing performed (e.g. molecular testing of tumor biopsy or circulating tumor DNA) 
the results of the testing will be recorded if available.  Patients who discontinue 
therapy for reasons other than disease progression will be followed for disease 
progression. The imaging schedule is at the discretion of the treating physician, but 
the recommended interval is every 6 to 12 weeks. 
 
8.5 End of Study 
 
The end of study will be defined as the time at which all patients have discontinued study 
therapy and study report is accepted for publication.  
 
 
8.6 Study Assessments 
 
8.6.1 Medical History 
 
The history will be reviewed, with the patient, using the health care provider notes (i.e. the 
investigator’s and/or designees note).  
 
 

 
 
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8.6.2 Physical Exam 
 
A directed physical examination will be performed at the visits as indicated in the time and 
events table. Performance status will be assessed at screening, prior to the first dose of study 
treatment, at the beginning of each cycle, and at discontinuation according to ECOG criteria as 
discussed in Appendix 1. 
 
9.0 INVESTIGATIONAL THERAPY  
 
9.1 Study Therapy 
 
AstraZeneca will supply osimertinib tablets for oral administration as a single daily dose of 80 
mg.  Tablets can be taken whole with approximately 240 ml water, with or without regard to 
food Study drugs will be taken by patients at home after they have received administration 
instructions. Doses should be taken approximately 24 hours apart at the same time-point each 
day.  
  
Doses should not be missed.  If a patient misses taking a scheduled dose, within a window of 12 
hours, it is acceptable to take the dose.  If it is more than 12 hours after the dose time, the missed 
dose should not be taken and patients should be instructed to take the next dose at the next 
scheduled time.  If a patient vomits after taking osimertinib, they should not make up for this 
dose, but should take the next scheduled dose.  The missed doses and reason should be recorded 
in the patient diary. 
 
A study cycle is defined as 28 consecutive days and patients will take their study drug on days 1-
28 of each cycle. Study drug may be interrupted up to 21 days. Additional information about the 
investigational product may be found in the IB for each agent. 
 
Investigational product 
Dosage form and strength 
Manufacturer 
Osimertinib 
40 mg tablet  
AstraZeneca 
Osimertinib 
80 mg tablet 
AstraZeneca 
 
Reported adverse events and potential risks are described in Section 2. No investigational or 
commercial agents or therapies other than those described in this study may be administered with 
the intent to treat the patient’s malignancy. All patients will be requested to maintain a 
medication diary of each dose of medication.  The medication diary will be returned to clinic 
staff at the end of each cycle. 
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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9.1.1 Dose Modification 
Dose delays and modifications will be made as indicated below. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will be utilized for dose delays and dose modifications. A copy of the CTCAE 
version 4.03 can be downloaded from the CTEP website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
1.  
If any patient experiences a CTCAE grade 3 or intolerable grade 2 adverse event related 
to osimertinib, dosing will be interrupted and supportive therapy administered as per 
institutional standard. Patients will not be permitted to restart osimertinib until toxicities 
have resolved to CTCAE grade ≤1.  
2.  
If grade 3 or intolerable adverse event does not resolve with 21 days, patient should 
permanently discontinue study therapy 
3.  
If first grade 3 or intolerable grade 2 adverse event which resolves within 21 days patient 
may restart at 80 mg dose level or 40 mg dose delay (at the discretion of the treating 
physician) 
4.  
If second grade 3 or intolerable grade 2 adverse event which resolves within 21 days 
patent must have dose reduced to 40 mg daily 
5.  
If patient is on 40 mg dose level and experiences a grade 3 or intolerable grade 2 adverse 
event patient must discontinue study therapy  
6.  
Patients experiencing corneal ulceration (any grade), interstitial lung disease (ILD), and 
QTc interval prolongation with signs/symptoms of serious arrhythmia will permanently 
discontinue the osimertinib.    
7.  
For patients with grade 3 QTc prolongation dose reduction to 40 mg daily is mandatory  
 
Patients who are unable to remain on study therapy because of toxicity should be considered for 
treatment, as per institutional standard. 
 
 
 

 
 
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Dose reduction schema for grade 3 or intolerable grade 2 adverse events.  
For specific management other than pulmonary, QTc prolongation, and corneal ulceration or 
grade 3 ophthalmologic adverse events please refer to table and text 
 
 
 
TABLE 2: DOSE REDUCTION 
 
 
    
 
 
 
 
9.1.2 Management of adverse effects 
 
Symptom-specific toxicity management  
 
Guidance for toxicity management will be as indicated below for patients enrolled, and 
investigators should manage toxicities per institutional standards and the specific clinical 
circumstances. Other toxicities should be managed as per institutional standards or at the 
discretion of the investigator. 
 
For additional details, please refer to the table and text below: 
 
Dose level 
Osimertinib dose 
Schedule 
“0” 
80 mg 
Daily 
“-1” 
40 mg 
Daily 

 
 
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TABLE 3 DOSE MODIFCATION GUIDELINES 
 
NCI-CTCAE (v4.03) 
Grade 
Dose Modification  
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at first 
onset, followed by 2 mg q2-4 hours 
until free of diarrhea for 12 hours, 
maximum daily dose of 16 mg/day). 
Grade 2 
None 
Loperamide (4 mg at first onset, 
followed by 2 mg every 2-4 hours 
until free of diarrhea for 12 hours, 
maximum daily dose of 16 mg/day).  
Grade 3 or intolerable 
grade 2 
Hold study treatment for 
up to 21 days 
Dose modification as noted, with 
supportive care per PI discretion.  
Grade 4 
Discontinue study 
treatment. 
Supportive care as per intuitional 
standard  
Rash 
Grade 1 and 2 tolerable 
rash 
None 
Any of the following, at the 
discretion of the investigator: 
1. Oral antibiotics (tetracycline, 
minocycline, doxycycline) 
2. Topical clindamycin, 
diphenhydramine, topical 
corticosteroids or emollient 
cream 
Grade 2 intolerable or 
grade 3 rash 
Study treatment 
interruption for up to 21 
days  
Manage as described above with 
both oral antibiotics and topical 
agent. Oral corticosteroids may be 
considered at the discretion of the 
investigator. 
Grade 4 
Discontinue study 
treatment 
Manage as described above with 
both oral antibiotics and topical 
agent. Oral corticosteroids may be 
considered at the discretion of the 
investigator. 
Paronychia 
 
 
Grade 1  
None 
Topical antibiotic bid and vinegar 
soaks (soaking finger or toes in a 1:1 
solution of white vinegar in water for 
15 minutes every day) 
Grade 2 
May continue at current 
dose or dose reduce at the 
discretion investigator 
Topical antibiotic BID and vinegar 
soaks as outline above 
Topical silver nitrate weekly 

 
 
40 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Grade 2 intolerable or 
grade 3 
Study treatment 
interruption for up to 21 
days 
Topical antibiotic bid and vinegar 
soaks as outline above 
Topical silver nitrate weekly 
Consider nail avulsion or removal 
Grade 4 
Discontinue study 
treatment 
 
Hepatic Transaminases and/or total bilirubin: please refer criteria for Hy’s law 
provided in appendix 3 
Grade 1 
None 
Observation 
Grade 2 
None 
Observation 
Grade 3 
Study treatment 
interruption for up to 21 
days 
Observation until laboratory values 
return to Grade 1 
Grade 4 
Discontinue study 
treatment 
 
Pulmonary Events if possibly Interstitial Lung Disease (ILD)  
All Grades 
Temporarily interrupt 
study treatment pending 
the diagnostic evaluation. 
If the pulmonary adverse 
event is felt to be related to 
osimertinib, then 
permanently discontinue 
osimertinib. 
Unexplained dyspnea, either new or 
progressive, should be thoroughly 
evaluated. Where ILD is suspected, 
administer corticosteroids at a dose 
of 1 to 2 mg/kg/day prednisone 
equivalents for Grade 2 or greater 
pneumonitis, followed by 
corticosteroid taper. 
Cardiac 
 
 
Grade 3 
QTc interval greater than 
500 msec on at least 2 
separate ECGs 
Withhold osimertinib until QTc 
interval is less than 481 msec or 
recovery to baseline if baseline QTc 
is greater than or equal to 481 msec, 
then restart at a reduced dose (40 
mg) 
Grade 4 
QTc interval greater than 
500 msec or > 60 msecs 
from baseline and with 
signs/symptoms of serious 
arrhythmia 
Permanently discontinue osimertinib 
Management of elevated creatine kinase: please check for drug-drug interactions and 
refer to appendix 2 for potential drug-drug interactions  
Grade 1 
None 
Observation (assess for drug-drug 
interactions contributing to 
elevation. Please refer to appendix 2)  
Grade 2 
None 
Observation (assess for drug-drug 
interactions contributing to 
elevation. Please refer to appendix 2) 

 
 
41 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Grade 3 
Study treatment 
interruption for up to 21 
days 
Observation until laboratory values 
return to Grade 1 (assess for drug-
drug interactions contributing to 
elevation. Please refer to appendix 2) 
 Grade 4 
Discontinue study 
treatment 
Discontinue study treatment  
Ocular  
 
 
 
Corneal ulceration  
Permanently discontinue osimertinib 
Grade > 3 or eye 
symptoms that are 
clinically significant 
and/or persistent (>7 
days) 
Referral to 
ophthalmologist 
 
 
 Permanently discontinue osimertinib 
Grade 4  
Referral to 
ophthalmologist 
Permanently discontinue osimertinib   
Other 
 
 
Grade ≥3 adverse event 
If Grade 3 or higher 
adverse reaction improves 
to grade ≤ 1 after 
withholding of osimertinib 
for up to 21 days 
Osimertinib may be restarted at the 
same dose (80 mg) or a lower dose 
(40 mg) at the discretion of the 
investigator  
 
If grade 3 or higher 
adverse reaction that does 
not improve to grade ≤ 1 
after withholding for up to 
21 days. 
Permanently discontinue osimertinib 
 
 
9.1.3  Definition of Evaluable Subjects, On Study, and End of Study 
 
All patients who receive a dose of the study medication (osimertinib) will be considered 
evaluable. Patients who withdraw consent before starting study medication, sign informed 
consent document and are subsequently found ineligible, or do not start study medication will 
not be a considered evaluable. Patients who start study medication and do not have a 
radiographic assessment due to clinical progression will be considered as having disease 
progression. Patients who have progressive disease, unacceptable toxicity, or withdraw consent 
will be considered as coming off study and the date of the most recent clinic visit or imaging will 
be considered the end of the study.  
 
 
 

 
 
42 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
9.1.4 Early Study Termination 
 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all 
subjects on study should be notified as soon as possible.  Additional procedures and/or follow up 
should occur in accordance with Section 13, which describes procedures and process for 
prematurely withdrawn patients. 
 
10.0 BLINDING 
 
This is an open-label study, therefore, each patient will be aware of his or her assigned study 
treatment.  All staff involved in treating and caring for study patients will have full knowledge of 
study treatment assignment for those patients under their care. 
 
11.0 CONCOMITANT MEDICATIONS 
 
The site PI should be alerted if the participant is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes.  Appendix 2 presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the counter (OTC), herbal supplements, and IV medications and 
fluids. 
 
All concomitant medications received within 30 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment are to be records. 
12.0 OTHER CONSIDERATIONS 
12.1 Contraception 
 
Female 
Being a part of this study while pregnant may expose the unborn child to significant risks, some 
of which may be currently unforeseeable.  Therefore, pregnant women will be excluded from the 
study.  Females of childbearing potential, if sexually active, must agree to use two forms of 
appropriate contraceptive measures from the time of screening, for the entire duration of the 
study and at least 6 weeks after discontinuing the study drug. Medically acceptable 
contraceptives include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) 
approved hormonal contraceptives (such as birth control pills, patches, implants or injections) 
that are not prone to drug-to-drug interactions (IUS Levonorgetrel Intra Uterine System (Mirena) 

 
 
43 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Medroxyprogresterone  injections (Depro-Provera), (3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive measures 
such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods 
for routine use.  If you do become pregnant during this study or if you have unprotected sex, you 
must inform your study physician immediately. 
 
Male 
Must agree to use a medically acceptable form of birth control in order to be in this study and for 
6  months afterward. Medically acceptable contraceptives include: (1) surgical sterilization (such 
as a vasectomy), or (2) a condom used with a spermicide.  Contraceptive measures such as Plan 
B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine 
use. Men should refrain from donating sperm from the start of dosing until 6 months after 
discontinuing study drug. You should inform your partner of the potential for harm to an unborn 
child.  She should know that if pregnancy occurs, you will need to report it to the study doctor, 
and she should promptly notify her doctor. 
12.1 Use in Pregnancy 
There are no or limited amount of data from the use of osimertinib in pregnant women. Studies 
in animals have shown reproductive toxicity. Based on its mechanism of action and preclinical 
data, osimertinib may cause fetal harm when administered to a pregnant woman. Administration 
of osimertinib to pregnant rats was associated with embryolethality, reduced fetal growth and 
neonatal death at exposures similar to what is expected in humans. Osimertinib is not 
recommended during pregnancy and in women of childbearing potential not using 
contraception. 
 
12.3  Use in Nursing Women 
It is not known whether osimertinib or its metabolites are excreted in human milk. 
Administration to rats during gestation and early lactation was associated with adverse effects, 
including reduced growth rates and neonatal death. There is insufficient information on the 
excretion of osimertinib or its metabolites in animal milk. A risk to the suckling child cannot be 
excluded.  Breast-feeding should discontinue during study treatment with osimertinib. 
 
12.4 Fertility 
There are no data on the effect of osimertinib on human fertility. Results from animal studies 
have shown that osimertinib has effects on male and female reproductive organs and could 
impair fertility. 
 
 

 
 
44 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
13.0 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
 
13.1 Criteria for Early Withdrawal 
 
A subject may be discontinued from the study for any of the following reasons.  The PI may also 
withdraw a subject from the study at any time based on his/her discretion 
 
- 
Subject or legal representative withdraws consent 
- 
Confirmed radiographic disease progression 
- 
There is toxicity deemed by the investigator or subject to be unacceptable 
- 
Concurrent illness that prevents further administration of treatment 
- 
The subject, for any reason, reason requires treatment with another systemic agent 
potentially effective for treatment of the study indication. In this case, 
discontinuation from the study occurs immediately upon introduction of the new 
agent 
- 
Noncompliance with trial treatment or procedure requirements 
- 
Abnormal laboratory values 
- 
Abnormal test procedure results 
- 
Protocol deviation 
- 
Administrative issues 
- 
Pregnancy 
- 
Subject is lost to follow-up 
- 
The investigator for any reason, stops the study 
- 
Termination of the study by AstraZeneca 
 
13.2 Follow-up Requirements for patients who discontinue therapy prior to disease        
progression 
 
Patients who do not start study drug will not have any study follow-up requirements. Patients 
who discontinue therapy for reasons other than disease progression will be followed for disease 
progression every 6-12 weeks at the discretion of the treating physician until disease progression 
and once patient stop study therapy they will be followed for overall survival every 3 months by 
telephone or by review medical records for a maximum of 2 years.  
 
13.3 Replacement of Early Withdrawal(s) 
 
Patients who do not start study drug will be replaced and will be considered non-evaluable. They 
will be classified as “consented but not treated.”   

 
 
45 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
13.4 Clinical Criteria for Early Trial Termination 
 
• Quality of quantity of data recording is inaccurate or incomplete 
• Poor adherence to protocol and regulatory requirements 
• Incidence of severity of adverse drug reaction in this or other studies indicate a potential 
health hazard to subjects. 
• Plans to modify or discontinue the development of the study drug 
 
13.5 Discontinuation of the Study 
 
This study can be terminated at any time for any reason by the PI-sponsor, Astrazenca or the 
IRB.  If this occurs, all subjects on study should be notified as soon as possible.  Additional 
procedures and/or follow-up should occur in accordance with Table 4. 
 
 
14.0 STUDY DRUG 
14.1 Names, Classification, and Mechanism of Action 
 
Osimertinib (AZD9291, Tagrisso) is a third generation EGFR TKI. It is potent irreversible 
inhibitor of both single EGFR activating mutations (TKI sensitivity-conferring mutations) and 
EGFR T790M mutations (TKI resistance mutations). As a result, osimertinib has the potential to 
provide clinical benefit to patients with advanced NSCLC harboring both the single sensitivity 
mutations and the T790M resistance mutation following prior therapy with an EGFR TKI. The 
molecular formula is C28H33N7O2. The molecular weight is 499.6 g/mol. 
 
14.2 Packaging and labeling  
 
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines. The labels will fulfill Good Manufacturing Practice Annex 13 requirements for 
labeling. The label will include the Name of the Sponsor, Study Code, For Clinical trial use only 
and /or any other market specific requirements. All study drugs should be kept in a secure place 
under appropriate storage conditions. The investigational product label on the pack specifies the 
appropriate storage.  
 
 
 

 
 
46 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
14.3 Supply, Receipt, and Storage 
 
Osimertinib should be stored at temperatures of 15°C and 30°C (59°F and 86°F). There are no 
special handling precautions or special equipment needed for handling or administration of this 
agent. Osimertinib will be provided by AstraZeneca free of charge and will be ordered through 
the research pharmacy. 
 
14.4 Dispensing and Preparation 
 
Osimertinib tablets will be supplied to the research pharmacy in white, high-density polyethylene 
(HDPE) bottles with child-resistant closures and should be stored at temperatures of 15°C and 
30°C (59°F and 86°F). Each bottle will contain 30 tablets but it is permissible for the research 
pharmacy to open stock bottles and dispense 30 tablets of either 40 or 80 mg to patients in 
standard amber prescription vials.   
 
14.5 Compliance and Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
14.6 Disposal and Destruction 
Unused osimertinib will be returned to the clinic study nurse at the indicated clinic visit and 
returned to the research pharmacy for disposal. 
 
15.0 COSTS TO THE SUBJECT 
 
There will be no additional cost to subjects as a result of being in this study.  AstraZeneca will 
provide the study drug, osimertinib, free of charge.  
 
Routine medical care given for the disease under study (which is care a subject would receive 
whether or not they were in this study), such as blood draws, will be charged to subject’s 
insurance company. 
 
 
 

 
 
47 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
16.0 SAFETY MONITORING AND REPORTING  
 
The PI at each institution is responsible for the identification and documentation of adverse events 
and serious adverse events, as defined below.  At each study visit, the PI or designee must assess, 
through non-suggestive inquiries of the subject or evaluation of study assessments, whether an AE or 
SAE has occurred.  Adverse events that are judged to be Serious Adverse Events by the institutional 
PI should be reported to the Duke Cancer Institute Safety Desk to their local Institutional IRBs in 
accordance with the reporting requirements.  
 
16.1 Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and 
which does not necessarily have a causal relationship with this study treatment.  For this 
protocol, the definition of AE also includes worsening of any pre-existing medical condition.  An 
AE can therefore be any unfavorable and unintended or worsening sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of study drug, 
whether or not related to use of the study drug.  Abnormal laboratory, physical exam or vital sign 
findings without clinical significance (based on the PI’s judgment) should not be recorded as 
AEs 
 
From the time that the subject signs the informed consent form through the End of Study 
Treatment visit (as defined in Section 8.3), all AEs must be recorded in the subject medical 
record and adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 4.03.  If CTCAE grading does not exist 
for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-
threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely:  The AE is doubtfully related to the study drug 
- 
Unrelated:  The AE is clearly NOT related to the study drug 
16.1.1. Reporting of AEs 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on 
the toxicity case report forms.  AEs reported through expedited processes (e.g., reported to 
the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 

 
 
48 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Abnormal laboratory results are to be records as AEs if any of the following conditions are 
met: 
• The abnormal laboratory value leads to a therapeutic intervention (e.g. corrective 
therapy). 
• The abnormal laboratory value is considered to be clinically significant by the 
Investigator. 
• Any lab test result that is clinically significant or meets the definition of an SAE. 
• Any laboratory test result abnormality that required the subject to have study 
treatment discontinued or interrupted 
 
16.2 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Astrazeneca’s product. An AE is considered “serious” if in the opinion of the investigator it is 
one of the following outcomes: 
 
- 
Results in death 
- 
Life-threatening 
- 
Constitutes a congenital anomaly or birth defect 
- 
A medically significant condition (defined as an event that compromises subject 
safety or may require medical or surgical intervention to prevent one of the three 
outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to conduct 
normal life functions. 
 
 
16.2.1 Serious Adverse Event Reporting 
 
Life-threatening (grade 4 or 5) SAEs, deaths, and unknown reactions or unexpected events that 
occur in the course of any patient’s treatment on study (from the time of enrollment) or within 30 
days following cessation of study treatment are reportable.  All sites will complete DCI SAE 
Report Form and Page 1 of the DCI Safety Review Form.   
 
Sub-sites will submit both forms to the DCI Safety Desk (Fax #: 919-681-9357 or email to 
dcccsafe@dm.duke.edu) and to the Lead PI, Dr. Stinchcombe (Fax: 919-684-8926 and 
scanned/emailed to the Thoracic Oncology Protocol Office Thoracic-multisite@dm.duke.edu). 
 
Note:  It is imperative that initial SAE reports are submitted as soon as possible (within 24 hours 
of knowledge of the event) with available information to the DCI Safety Desk.  Missing and/or 
clarified event information may be provided in a follow-up report.   
 

 
 
49 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
If the safety desk cannot be reached within 24 hours, the Duke PI, Dr. Thomas 
Stinchcombe, should be contacted (thomas.stinchcombe@duke.edu, Pager (919) 970- 2829, 
Office: (919) 681-9509. 
 
The initial report for each SAE or death should include at minimum the following information: 
• protocol # and title 
• patient initials, study identification number, sex, age 
• date the event occurred 
• description of the SAE 
• dose level and cycle number at the time the SAE occurred 
• description of the patient’s condition 
• indication whether the patient remains on study 
• causality or causal relationship 
 
De-identified source documentation (i.e. admission notes, discharge notes, applicable laboratory 
results, radiology/diagnostic testing results, etc.) must be sent with the SAE Report Form. 
Follow-up information including severity, action taken, concomitant medications, and outcome 
should be communicated to Duke as soon as possible using the same forms mentioned above. 
The Lead PI or designee will complete Page 2 of the DCI Safety Review Form and promptly 
submit it to the DCI Safety Desk.  The DCI Safety Desk will forward the information from the 
SAE report and the PI’s Assessment of the SAE to the Duke University IRB if it meets reporting 
requirements. 
 
Reporting to the FDA   
 
Duke as the lead center is responsible for reporting the serious adverse event to the FDA in 
accordance with 21CFR 312.32.  Any SAE that is possibly related and unexpected must be 
submitted to the FDA attached to the IND.  This will be done by DCI Safety Desk and/or 
coordinate with study team regulatory coordinator. 
Reporting SAEs at participating institutions  
 
Each site is responsible for reporting unexpected and/or serious adverse events to their individual 
IRB. 
 
Expedited Reporting Procedure for Duke Cancer Institute (Coordinating Center): 
Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs 
to the FDA in accordance with 21CFR 312.32.  Any SAE that is possibly related and unexpected 
must be submitted to the FDA attached to the IND.  If the SAE meets criteria for reporting to the 
FDA, the DCI Safety Desk will complete the Form FDA 3500A (MedWatch) and send to the 

 
 
50 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
Principal Investigator and the Sponsor that are noted above.  This submission of the Form FDA 
3500A to the FDA attached to the IND will be completed by the designee. 
• All unexpected, drug related SAEs that are fatal or life-threatening will be reported to 
the FDA by phone or fax within 7 calendar days of initial receipt of the information 
and will provide a complete report within 8 days of the initial report submission (by 
calendar day 15).  
• All unexpected, study treatment-related SAEs that are not fatal or life-threatening will 
be reported in a written report to the FDA within 15 days of initial receipt of the 
information 
 
Reporting of SAEs  
Process for Reporting of SAEs to Duke: 
 
When an SAE or pregnancy/lactation occurs at a participating site, the responsible coordinator 
will report the event to the Duke Cancer Institute Safety Desk within 24 hours using the DCI 
SAE Notification and Report Form.  Adverse events (non-serious) are to be appropriately 
recorded in the case report forms, but are not reported to the DCI Safety Desk.  
 
The Duke Safety Desk will conduct a preliminary review of the information to confirm 
expectedness and reporting to the Duke IRB. The Duke PI is responsible for causality assessment 
and final determination of reportability. The Duke PI will complete Page 2 of the DCI Safety 
Review Form and promptly submit it to the DCI Safety Desk.  
 
The DCI Safety Desk will forward the information from the SAE report and the PI’s Assessment 
of the SAE to the Duke University IRB, if it meets reporting requirements. Each institution is 
responsible for reporting SAEs to their local institutional IRBs in accordance with 
reporting requirements.  
 
In addition to the DCI Safety Notification form and the SAE PI Assessment Review form (page 
1), the initial report for each SAE or death should include at a minimum the following 
information: 
• Protocol number (TOP 1703, Pro00088376) 
• Patient initials, study identification number, sex, age 
• Date the event occurred 
• Description of the SAE 
• Dose level and cycle number at the time the SAE occurred 
• Description of the patient’s condition.  

 
 
51 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
• Indication whether the patient remains on study 
• Causality or causal relationship 
 
De-identified source documentation (admission notes, discharge notes, applicable laboratory 
results, radiology/diagnostic testing results, etc.) must be sent with the SAE Report Form. 
Follow-up information including severity, action taken, concomitant medications, and outcome 
should be communicated to Duke as soon as possible using the same forms mentioned above.  
 
REPORTING SAEs to ASTRAZENECA and the FDA: 
 
The Duke Safety Desk will be responsible for reporting SAEs and reports of pregnancy/lactation 
to AstraZeneca within 2 working days (provider of investigational compound) and for any 
follow-up information requested by AstraZeneca.  
 
The Duke Safety Desk will complete Form 3500A (21CFR 312.32) as needed.  
 
16.2.2   Protocol Specific Exceptions to Serious Adverse Event Reporting 
Events which are unequivocally due to disease progression should not be reported as an AE 
during the study 
 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered 
an SAE. 
 
16.3 Safety Oversight Committee (SOC) 
 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of 
DUHS sponsor-investigator phase I and II, therapeutic interventional studies that do not have 
an independent Data Safety Monitoring Board (DSMB). The primary focus of the SOC is 
review of safety data, toxicities and new information that may affect subject safety or 
efficacy. Annual safety reviews includes but may not be limited to review of safety data, 
enrollment status, stopping rules if applicable, accrual, toxicities, reference literature, and 
interim analyses as provided by the sponsor-investigator.  The SOC in concert with the DCI 
Monitoring Team (see Section 17.1 for Monitoring Team description) oversees the conduct 
of DUHS cancer-related, sponsor-investigator greater-than-minimal-risk intervention studies 
that do not have an external monitoring plan, ensuring subject safety and that the protocol is 
conducted, recorded and reported in accordance with the protocol, standing operating 
procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements. 
 

 
 
52 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
17.0 QUALITY CONTROL AND QUALITY ASSURANCE 
 
17.1 Monitoring 
 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure 
subject safety and to ensure that the protocol is conducted, recorded, and reported in accordance 
with the protocol, standard operating procedures, good clinical practice, and applicable 
regulatory requirements.  As specified in the DCI Data and Safety Monitoring Plan, the DCI 
Monitoring Team will conduct routine monitoring after the third subject is enrolled, followed by 
annual monitoring of 1 – 3 subjects until the study is closed to enrollment and subjects are no 
longer receiving study interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon 
request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight 
Committee (SOC), the sponsor, the PI, or the IRB.  All study documents must be made available 
upon request to the DCI Monitoring Team and other authorized regulatory authorities, including 
but not limited to the National Institute of Health, National Cancer Institute, and the FDA.  Every 
reasonable effort will be made to maintain confidentiality during study monitoring. 
 
Please refer to the study specific external site monitoring plan for monitoring sites external to the 
Duke University Heath System.  
 
17.2 Audits  
 
The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) may conduct 
confidential audits to evaluate compliance with the protocol and the principles of GCP.  The PI 
agrees to allow the OARC auditor(s) direct access to all relevant documents and to allocate 
his/her time and the time of the study team to the OARC auditor(s) in order to discuss findings 
and any relevant issues. 
 
OARC audits are designed to protect the rights and well-being of human research subjects. 
OARC audits may be routine or directed (for cause). Routine audits are selected based upon risk 
metrics generally geared towards high subject enrollment, studies with limited oversight or 
monitoring, Investigator initiated Investigational Drugs or Devices, federally-funded studies, 
high degree of risk (based upon adverse events, type of study, or vulnerable populations), Phase I 
studies, or studies that involve Medicare populations. Directed audits occur at the directive of the 
IRB or an authorized Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to 
assess whether the research is conducted according to the protocol approved by the DUHS IRB. 

 
 
53 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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The primary purpose of the audit/review is to verify that the standards for safety of human 
subjects in clinical trials and the quality of data produced by the clinical trial research are met. 
The audit/review will serve as a quality assurance measure, internal to the institution. Additional 
goals of such audits are to detect both random and systemic errors occurring during the conduct 
of clinical research and to emphasize “best practices” in the research/clinical trials environment. 
 
18 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
 
18.1 Regulatory and Ethical Compliance 
 
This protocol was designed and will be conducted and reported in accordance with the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations. 
 
18.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
 
The protocol, informed consent form, advertising material, and additional protocol-related 
documents must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer 
Protocol Committee (CPC) for review.  The study may be initiated only after the PI has received 
written and dated approval from the CPC and IRB. 
 
The PI must submit and obtain approval from the IRB for all subsequent protocol amendments 
and changes to the informed consent form.  The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting 
subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
 
The PI must obtain protocol re-approval from the IRB within 1 year of the most recent IRB 
approval.  The PI must also obtain protocol re-approval from the CPC within 1 year of the most 
recent IRB approval, for as long as the protocol remains open to subject enrollment. 
 
18.3 Informed Consent 
 
The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
 
The PI or authorized key personnel will discuss with the potential subject the purpose of the 
research, methods, potential risks and benefits, subject concerns, and other study-related matters.  
This discussion will occur in a location that ensures subject privacy and in a manner that 
minimizes the possibility of coercion.  Appropriate accommodations will be made available for 
potential subjects who cannot read or understand English or are visually impaired.  Potential 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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subjects will have the opportunity to contact the PI or authorized key personnel with questions, 
and will be given as much time as needed to make an informed decision about participation in 
the study. 
 
Before conducting any study-specific procedures, the PI must obtain written informed consent 
from the subject or a legally acceptable representative.  The original informed consent form will 
be stored with the subject’s study records, and a copy of the informed consent form will be 
provided to the subject.  The PI is responsible for asking the subject whether the subject wishes 
to notify his/her primary care physician about participation in the study.  If the subject agrees to 
such notification, the Principal Investigator will inform the subject’s primary care physician 
about the subject’s participation in the clinical study. 
 
 
18.4 Data and Safety Monitoring 
 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety 
Monitoring Plan (DSMP).  For a more detailed description of the DSMP for this protocol, refer 
to Sections 16.3 and Section 17.1. 
 
18.5 Protocol Amendments 
 
All protocol amendments must be initiated by the PI and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the 
safety of a subject from an immediate hazard.  However, the PI must inform the IRB and all 
other applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC should be informed about any protocol amendments that 
potentially affect research design or data analysis (i.e. amendments affecting subject population, 
inclusion/exclusion criteria, agent administration, etc.). 
 
18.6 Publication Plan 
 
The results will be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. A report is planned to be published in a peer-reviewed journal, thus the 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes is planned to be made public no later than 
three (3) years after the end of the study. 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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19 Privacy, Confidentiality, and Data Storage 
 
The PI will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate 
institutional Site Based Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects 
during the course of the study.  Prospective participants will be consented in an exam room 
where it is just the research staff, the patient and his family, if desired. For all future visits, 
interactions with research staff (study doctor and study coordinators) regarding research 
activities will take place in a private exam room. All research related interactions with the 
participant will be conducted by qualified research staff who are directly involved in the conduct 
of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under 
lock and key accessible only by the research staff. Subjects will be identified only by a unique 
study number and subject initials.  Electronic records of subject data will be maintained using a 
dedicated database (MediData RAVE) which is housed in an encrypted and password-protected, 
DCI file server.  Access to electronic databases will be limited to authorized key personnel only.  
Subject data may be stored temporarily on encrypted and password-protected portable memory 
devices such as flash drives and external hard drives, but only when absolutely necessary.  Data 
stored on portable memory devices will be de-identified.  Subject data will be deleted from the 
portable memory device at the earliest opportunity.  The security and viability of the IT 
infrastructure will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP 
policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
 
20 Data Collection and Maintenance 
 
20.1 Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms, 
monitoring logs, appointment schedules, study team correspondence with PI-sponsor or 
regulatory bodies/committees, regulatory documents that can be found in the DCI-mandated 
“Regulatory Binder”, which includes but is not limited to signed protocol and amendments, 
approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory 
certifications and clinical supplies receipts and distribution records (if applicable). 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
 
Source documents are original records that contain source data, which is all information in 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source documents include but are not limited 
to hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification of being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial. When possible, the original record should be retained as the source document.  However, a 
photocopy is acceptable provided that it is a clear, legible and exact duplication of the original 
document. 
 
The research nurse, research coordinator, data manager and PI are responsible for ensuring that 
data extraction (information required by the protocol) is completed in a timely manner for every 
patient enrolled on study.  The following forms are an integral part of the study data and will be 
maintained in the patients’ clinical or research chart in accordance with the institutions practice.  
Any errors on the forms should be lined through, but not obliterated with the correction inserted, 
initialed and date by the person making the correction 
 
• Eligibility checklist 
• Serious and non-serious adverse evert forms (if applicable) 
• Protocol Deviation Form (if applicable) 
20.2 Case Report Forms (CRFs) 
 
The electronic CRF will be the primary data collection document for the study.  The CRFs will 
be updated within two weeks of acquisition of new source data.  The electronic records of 
subject data will be maintained using a dedicated database (Medidata Rave and/or Redcap) 
which is housed in an encrypted and password protected DCI file server.  Access to electronic 
databases will be limited to the PI and designated stud staff listed on key personnel.  Subject data 
may be stored temporarily on encrypted and password-protected portable memory devices such 
as flash drives and external hard drives, but only when absolutely necessary.  Data stored on 
portable memory deviced will be de-identified.  Subject data will be deleted from the portable 
memory device at the earliest opportunity. The security and viability of the IT infrastructure will 
be managed by the DCI and/or Duke Medicine. Only approved study staff, are permitted to make 
entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system 
(Medidata Rave and/or Redcap).  Designated personnel will complete user training, as required 
or appropriate per regulations 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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20.3 Data Management Procedures and Data Verification 
 
Designated personnel using the electronic CRF will have access based on their specific roles in 
the protocol.  
 
Completeness of entered data will be checked automatically by the eCRF system, and users will 
be alerted to the presence of data inconsistencies.  Additionally, the data manager and will cross-
reference the data to verify accuracy.  Missing or implausible data will be highlighted for the PI 
requiring appropriate responses (i.e. confirmation of data, correction of data, completion or 
confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only 
after resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to 
the data. 
 
21 Study Closure 
 
Following completion of the studies, the PI will be responsible for ensuring the following 
activities: 
 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
        
Upon completion of the study, research records will be archived and handled per DUHS (or 
participating Institution’s) HRPP policy. 
 
21.1 Records Retention 
 
The Principal Investigator will maintain study-related records for the longer period of: 
 
• At least two years after the date on which a New Drug Application is approved by 
the FDA (if an IND is involved). 
• At least two years after formal withdrawal of the IND associated with this protocol 
(if an IND is involved). 
• At least six years after study completion (Duke policy). 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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22 STATISTICAL METHODS AND DATA ANALYSIS 
 
22.1 Analysis Sets  
 
The efficacy and safety analysis set consists of all patients who receive at least one dose of 
osimertinib and it will be used to analyze safety and efficacy endpoints, including objective 
response rate, progression-free survival and overall survival. Patients who withdraw prior to 
study treatment or fail to receive study treatment for various reasons, will not be included in the 
efficacy and safety analysis. 
 
22.2 Patient Demographics and Other Baseline Characteristics 
 
Standard demographic information (age, gender, etc.) and prior therapies, smoking history and 
specific mutation type will be collected.  
 
22.3 Study Treatments 
 
Osimertinib 80 mg daily until disease progression, unacceptable toxicity or withdraw of consent.  
 
22.4 Primary Objective 
 
Objective response rate, defined as all patients with a confirmed partial or complete response as 
assessed by investigator using RECIST 1.1 
 
22.4.1 Variable 
The primary outcome will be objective response rate as assessed by the investigator 
using RECIST 1.1 (appendix 3). Patients with confirmed partial or complete responses 
will be considered responders and patients without a partial or complete response will 
be considered non-responders.  
 
22.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The single-arm phase II trial is designed to test the following hypothesis about the anti-
tumor activity of the experimental therapy: 
 
H0: ORR <= 20% versus H1: ORR >= 40%, 
 
where ORR is the true ORR for the experimental therapy. We will use Simon’s optimal 
2-stage design to evaluate the ORR.27 The 2-stage design allow a futility test after stage 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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I patients has been evaluated for tumor response. The specific design described below 
is also the design that yields the smallest expected sample size under the null 
hypothesis (optimal) among all designs satisfying type I error of 0.10 and type II error 
of 0.10. 
 
Specifically, the first stage will enroll 17 patients. If there are 3 or fewer patients 
confirmed responders (complete or partial response) among the 17 patients, the trial 
will be terminated; otherwise, the trial will move forward to enroll additional 20 
patients. If 10 or fewer patients among the total of 37 patients are confirmed 
responders, the experimental therapy will be concluded as not worthy of further 
investigation; otherwise it will be conducted that the experimental therapy has 
sufficient activity worthy of further investigation. The above design has expected 
sample size 26 under the null hypothesis. The early stopping probability at stage I is 
0.5489 under the null hypothesis. The actual type I and type II errors are 0.0948 and 
0.0967, respectively.  
 
Patient characteristics at baseline will be summarized in tables and graphs. Categorical 
data will be summarized using frequency tables while summary statistics such as 
means, medians, standard deviation, range, etc. will be provided for continuous data.  
 
All enrolled patients, except for those withdrawn prior to study treatment or fail to 
receive study treatment for various reasons, will be included in the efficacy analysis. 
The primary endpoint will be objective response rate (ORR) per RECIST 1.1. Patients 
with confirmed partial or complete responses will be considered responders and 
patients without a confirmed partial or complete response will be considered non-
responders. Patients who stop therapy prior to confirmation of response per RECIST 
will be considered non-responders. Patients who are not able to get radiographic 
assessment for all reasons will be considered non-responders. At the end of the trial, the 
ORR will be estimated using the UMVUE method, and the p-value and 95% 
confidence interval will calculated.28,29 
 
22.4.3 Handling of missing values, censoring, and discontinuations 
 
Ineligible subjects and subjects who cancel registration before receiving any therapy 
will not be included in the efficacy analyses. Patients who receive at least one dose of 
the experimental therapy will be included in the safety analysis. 
 
22.5 Secondary Objectives 
 

 
 
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authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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22.5.1 Key Secondary Objectives  
 
1. Progression free survival using RECIST 1.1 as assessed by the investigator. 
Progression will be defined as time from start of study therapy to disease 
progression or death (whichever occurs first)  
2. Safety using CTCAE version 4.03 
3. Overall survival from start of study therapy to death (any cause) 
 
22.5.2 Exploratory Objectives  
1. Estimate the response rate and PFS in the specific mutation subsets of exon 18 
G719X, exon 20 S7681, exon 21 L861Q or compound mutations 
 
22.5.3 Statistical Analysis for Secondary Objectives 
 
Patients who are not able to get radiographic assessment for all reasons will be 
considered disease progression at the time they discontinue protocol therapy for the 
PFS analysis. Patients who stop therapy for reasons other than disease progression will 
be followed for disease progression. Patients who have not experienced an event of 
interest by the time of analysis will be censored at the date they are last known to be 
alive and progression-free. Overall survival is defined as the time from start of study 
therapy to death from any cause, and patients who are alive at the time of analysis will 
be censored at the last date of contact. Time to event endpoints will be summarized 
using the method of Kaplan and Meier as well as by Cox regression in the presence of 
covariates. Potential co-variates including smoking history, mutation subtype, gender, 
and performance status.  
 
An exploratory subset analysis will estimate the objective response rate, PFS and OS in 
the specific mutation subsets of exon 18 G719X, exon 20 S7681, exon 21 L861Q or 
compound mutations. 
 
The evaluation of safety using the AE using NCI CTCAE version 4.03. All patients 
who receive at least one dose of study treatment will be included in the safety analysis.  
 
22.6 Interim Analysis 
 
An interim analysis will be performed for efficacy part of the 2-stage design as outlined in 
section 22.4.2 
 
 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
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Protocol TOP 1703 
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22.7 Accrual and Follow-Up 
 
Taking into 5% ineligibility/cancelation rate, we will enroll approximately 39 patients to have 37 
evaluable patients for the efficacy analysis of the trial. At a rate of 1 to 2 patients per month, we 
expect that trial will take approximately 19-37 months to reach its target of 37 evaluable patients 
if it will not be terminated earlier based on the planned interim analysis.  All patients will be 
followed for disease progression and mortality from the date that the subjects were registered on 
study. Once patients are no longer on study therapy, they will be followed for overall survival for 
a maximum 2 years from discontinuation of study therapy.  
 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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23 REFERENCES 
 
1. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
2. 
Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med 361:947-57, 2009 
3. 
Rosell R, Carcereny E, Gervais R, 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 13:239-46, 2012 
4. 
Sequist LV, Yang JC, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus 
pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J 
Clin Oncol 31:3327-34, 2013 
5. 
Wu YL, Zhou C, Hu CP, et al: Afatinib versus cisplatin plus gemcitabine for first-line 
treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR 
mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213-
22, 2014 
6. 
Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in 
lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014 
7. 
Barlesi F, Mazieres J, Merlio JP, et al: Routine molecular profiling of patients with 
advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the 
French Cooperative Thoracic Intergroup (IFCT). Lancet 387:1415-26, 2016 
8. 
Costa DB: Kinase inhibitor-responsive genotypes in EGFR mutated lung 
adenocarcinomas: moving past common point mutations or indels into uncommon kinase 
domain duplications and rearrangements. Transl Lung Cancer Res 5:331-7, 2016 
9. 
Yang JC, Sequist LV, Geater SL, et al: Clinical activity of afatinib in patients with 
advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a 
combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet 
Oncol 16:830-8, 2015 
10. 
Park K, Tan EH, O'Byrne K, et al: Afatinib versus gefitinib as first-line treatment of 
patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 
2B, open-label, randomised controlled trial. Lancet Oncol 17:577-89, 2016 
11. 
Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus Chemotherapy 
for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823-1833, 2016 
12. 
Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 
2016 
13. 
Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 
14. 
Rittmeyer A, Barlesi F, Waterkamp D, et al: Atezolizumab versus docetaxel in patients 
with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, 
multicentre randomised controlled trial. Lancet 389:255-265, 2017 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
Version 2.0, 1 May 2018 
15. 
Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet 387:1540-50, 2016 
16. 
Janne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell 
lung cancer. N Engl J Med 372:1689-99, 2015 
17. 
Goss G, Tsai CM, Shepherd FA, et al: Osimertinib for pretreated EGFR Thr790Met-
positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, 
single-arm, phase 2 study. Lancet Oncol 17:1643-1652, 2016 
18. 
Mok TS, Wu YL, Ahn MJ, et al: Osimertinib or Platinum-Pemetrexed in EGFR T790M-
Positive Lung Cancer. N Engl J Med, 2016 
19. 
Yasuda H, Park E, Yun CH, et al: Structural, biochemical, and clinical characterization of 
epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci 
Transl Med 5:216ra177, 2013 
20. 
Hirsch FR, Scagliotti GV, Mulshine JL, et al: Lung cancer: current therapies and new 
targeted treatments. Lancet 389:299-311, 2017 
21. 
Yang JC, Sequist LV, Zhou C, et al: Effect of dose adjustment on the safety and efficacy 
of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the 
randomized LUX-Lung 3 and 6 trials. Ann Oncol 27:2103-2110, 2016 
22. 
Yeh P, Chen H, Andrews J, et al: DNA-Mutation Inventory to Refine and Enhance 
Cancer Treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable 
genome-directed anticancer therapy. Clin Cancer Res 19:1894-901, 2013 
23. 
Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus 
chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression 
on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 16:990-8, 
2015 
24. 
Gainor JF, Shaw AT, Sequist LV, et al: EGFR Mutations and ALK Rearrangements Are 
Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell 
Lung Cancer: A Retrospective Analysis. Clin Cancer Res 22:4585-93, 2016 
25. 
Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-
8, 2015 
26. 
Heuckmann JM, Rauh D, Thomas RK: Epidermal growth factor receptor (EGFR) 
signaling and covalent EGFR inhibition in lung cancer. J Clin Oncol 30:3417-20, 2012 
27. 
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-
10, 1989 
28. 
Jung SH, Kim KM: On the estimation of the binomial probability in multistage clinical 
trials. Stat Med 23:881-96, 2004 
29. 
Koyama T, Chen H: Proper inference from Simon's two-stage designs. Stat Med 
27:3145-54, 2008 
 
 
 
 
 
 

 
 
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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1703 
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24 LIST OF APPENDICES 
 
Appendix 1 
Performance Status Criteria: ECOG 
Appendix 2 
Information on Possible Drug Interactions Osimertinib 
Appendix 3 
Actions Required in Cases of Combined Increase of Aminotransferase and Total 
Bilirubin - Hy’s Law.  
Appendix 4 
Measurement of Effect 
Appendix 5 
Standard Cockcroft and Gault Formula for Calculated Creatinine Clearance 

 
 
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required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
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Protocol TOP 1703 
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24.1 APPENDIX 1: Performance Status Criteria: ECOG 
 
Grade 
Description  
0 
Fully active, able to carry on all predisease 
activities without restriction 
(Karnofsky 90-100). 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light 
housework, office work (Karnofsky 70-80). 
2 
Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up 
and about more than 50 percent of waking 
hours  
(Karnofsky 50-60). 
3 
Capable of only limited self-care, confined to 
bed or chair 50 percent or more of waking 
hours  
(Karnofsky 30-40). 
4 
Completely disabled. Cannot carry on any 
self-care. Totally confined to bed or chair  
(Karnofsky 10-20) 
5 
Dead 
 
 
 

 
 
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24.2 APPENDIX 2: Information on Possible Drug Interactions Osimertinib 
 
The use of any natural/herbal products or other “folk remedies” should be discouraged, but use of these products, as 
well as use of all vitamins, nutritional supplements, and all other concomitant medications must be recorded in the 
electronic case report form (eCRF). 
1. Drugs Inducing CYP3A4 Metabolism That AstraZeneca Strongly Recommend Are Not Combined With 
Osimertinib 
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes. 
 
A drug-drug interaction study of osimertinib evaluated in patients showed that there is potential for osimertinib 
being a victim when co-administered with strong inducers of CYP3A4 (osimertinib concentrations are decreased 
when co-dosed with rifampicin). 
 
The following potent inducers of CYP3A4 must not be used during this study for any patient receiving osimertinib. 
Table 1: Drugs Inducing CYP3A4 
Contraindicated drugs 
Withdrawal period prior to osimertinib start 
Carbamazepine, phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentin 
St John’s Wort 
3 weeks 
Phenobarbitone 
5 weeks 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that are known to 
strongly modulate CYP3A4 activity.  Appropriate medical judgment is required.  Please contact AstraZeneca with 
any queries you have on this issue. 
2. Medicines Whose Exposures May be Affected by Osimertinib That AstraZeneca Considers May be 
Allowed With Caution 
Osimertinib may increase the concentration of sensitive breast cancer resistance protein (BCRP) substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin, is increased). 
Table 2: Exposure, Pharmacological Action and Toxicity May be Increased by Osimertinib 
Warning of possible interaction 
Advice 
Rosuvastatin 
Drugs are permitted but caution should be exercised and patients 
monitored closely for possible drug interactions.  Please refer to full 
prescribing information for all drugs prior to co-administration with 
osimertinib. 
Sulfasalazine 
Doxorubicin 
Daunorubicin 
Topotecan 
 
3. Drugs That May Prolong QT Interval 
The drugs listed in this section are taken from information provided by The Arizona Center for Education and 
Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and Rockville, Maryland. Ref:  
http://www.arizonacert.org/medical-pros/drug-lists/drug lists.htm. 

 
 
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3.1 Drugs known to prolong QT interval 
The following drugs are known to prolong QT interval or induce Torsades de Pointes and should not be combined 
with osimertinib.  Recommended withdrawal periods following cessation of treatment with these agents are 
provided in the table. 
Table 3: Drugs Prolonging QT Interval 
Contraindicated drug 
Withdrawal period prior to osimertinib start 
Clarithromycin, droperidol, erythromycin, 
procainamide 
2 days 
Cisapride, disopyramide, dofetilide, domperidone, 
ibutilide, quinidine, sotalol, sparfloxacin, thioridazine 
7 days 
Bepridil, chlorpromazine, halofantrine, haloperidol, 
mesoridazine 
14 days 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide 
6 weeks a 
Pentamidine 
8 weeks 
Amiodarone, chloroquine 
1 year 
a 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied. 
 
3.2 Drugs that may possibly prolong QT interval 
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions) provided the patient 
has been stable on therapy for the periods indicated. 
Table 4: Drugs That May Prolong QT Interval 
Drug 
Minimum treatment period on medication 
prior to osimertinib start 
Alfuzosin, chloral hydrate, ciprofloxacin, dolasetron, foscarnet, 
galantamine, gemifloxacin, isridipine, ketoconazole, 
levofloxacin, mexiletine, nicardipine, octreotide, ofloxacin, 
ondansetron, quetiapine, ranolazine, telithromycin, tizanidine, 
vardenafil, venlafaxine, ziprasidone 
2 days 
Amantadine, amitriptyline, amoxapine, clozapine, doxepin, 
felbamate, flecainide, fluconazole, fosphenytoin, gatifloxacin, 
granisetron, imipramine, indapamide, lithium, 
moexipril/HCTZ, moxifloxacin, risperidone, roxithromycin, 
sertraline, trimethoprin-sulfa, trimipramine, voriconazole 
7 days 
Azithromycin, citalopram, clomipramine, itraconazole, 
nortriptyline, paroxetine, solifenacin, tacrolimus 
14 days 
Fluoxetine  
5 weeks 
Protriptyline 
6 weeks 
Tamoxifen 
8 weeks 
 
 

 
 
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24.3 APPENDIX 3: Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law  
 
1. INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
 
2. DEFINITIONS 
 
Potential Hy’s Law (PHL) 
 
A Potential Hy’s Law (PHL) case is defined as a study subject with an increase in serum 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN)  together with Total Bilirubin (TBL) ≥ 2xULN irrespective of serum Alkaline 
Phosphatase (ALP), at any point during the study following the start of study medication. 
 
Hy’s Law (HL) 
 
A Hy’s Law (HL) case is defined as a study subject with an increase in serum AST or ALT ≥ 3x 
ULN together with TBL ≥ 2xULN, where no other reason can be found to explain the 
combination of increases, e.g. elevated serum ALP indicating cholestasis, viral hepatitis, another 
drug. 
For PHL and HL to be met the elevation in transaminases must precede or be coincident with 
(i.e. on the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
 
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3xULN 
•  AST ≥ 3xULN 

 
 
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• TBL ≥ 2xULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits 
• Promptly enter the laboratory data into the laboratory CRF. 
 
4. FOLLOW-UP 
 
4.1 Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
 
• Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol. 
 
4.2 Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• Determine whether PHL criteria were met at any study visit prior to starting study 
treatment in the presence of liver metastases (See Section 6). 
• Notify the AstraZeneca representative who will then inform the central Study Team  
• The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  
Subsequent to this contact the Investigator will: 
• Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
• Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 
• Complete the three Liver CRF Modules as information becomes available. 
• If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
 
5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Medical Science Director and Global Safety Physician will also be involved in this 
review together with other subject matter experts as appropriate.  
 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 

 
 
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If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
 
• If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
 
• Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  
• The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
• As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review. 
 
6. ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA ARE MET 
BEFORE AND AFTER STARTING STUDY TREATMENT  
 
This section is applicable to subjects who meet PHL criteria on study treatment (including the 28 
day follow-up period post discontinuation of study treatment) having previously met PHL 
criteria at a study visit prior to starting study treatment.  
 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 
 
• Determine if there has been a significant change in the subjects’ condition compared with 
the last visit where PHL criteria were met 
• If there is no significant change no action is required 

 
 
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• If there is a significant change notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section 4.2 of this 
Appendix. 
 
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms such as fatigue, 
vomiting, rash, right upper quadrant pain, jaundice, eosinophilia.  The determination of whether 
there has been a significant change will be at the discretion of the Investigator; this may be in 
consultation with the Study Physician if there is any uncertainty. 
 
7. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
 
This section is applicable when a patient meets PHL criteria on study treatment (including the 
28-day follow-up period) and has already met PHL criteria at a previous on study treatment visit. 
 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.   
 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
 
• Was the alternative cause for the previous occurrence of PHL criteria being met chronic 
or progressing malignant disease or did the patient meet PHL criteria prior to starting 
study treatment and at their first on study treatment visit as described in Section 6? 
 
If No: Follow the process described in Section 4.2 of this Appendix 
 
If Yes: Determine if there has been a significant change in the patient’s condition compared with 
when PHL criteria were previously met 
 
• If there is no significant change no action is required 
• If there is a significant change follow the process described in Section 6 of this Appendix 
 
A ‘significant’ change in the patient’s condition refers to a subsequent clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms, such as fatigue, 
vomiting, rash, right upper quadrant pain, jaundice, eosinophilia.  The determination of whether 
there has been a significant change will be at the discretion of the Investigator; this may be in 
consultation with the Study Physician if there is any uncertainty. 
 
8. REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 

 
 
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24.4 APPENDIX 4: Measure of Effect 
 
Although response is the primary endpoint of this trial, participants with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, participants should be re-
evaluated every as per time and events table in section 8.  
 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1).1.  Changes in the largest diameter (unidimensional measurement) of the tumor lesions and 
the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one dose of study therapy, and have had 
their disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one dose of study therapy, and have had their disease re-evaluated will 
be considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are considered 
measurable if the lesion is not in bone.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 

 
 
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are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 

 
 
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followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 

 
 
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fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (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.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 

 
 
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Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or PI). 
 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
 
 
 
 
 
 
 

 
 
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For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 

 
 
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date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 

 
 
7 9 
T h e i nf or m ati o n c o nt ai n e d i n t his d oc u m e nt is r e g ar d e d as c o nf i d e nti al, a n d m ay n ot b e discl os e d t o a n ot h er p arty u nl ess s uc h discl os ur e is 
r e q uir e d t o i niti at e t h e st u dy, t o c o n d uct st u dy-r el at e d activiti es, or t o c o m ply wit h n ati o n al, st at e, or l oc al l a ws a n d r e g ulati o ns.  Writt e n 
a ut h oriz ati o n fr o m t h e c o or di n ati n g sit e a n d s p o ns or is r e q uir e d f or discl os ur e ot h er wis e. 
P ro to co l T O P  1 7 0 3  
ro to co l T O P  1 7 0 3  
V e rsio n  2 .0 , 1  M a y 2 0 1 8
V e rsio n  2 .0 , 1  M a y 2 0 1 8  
2 5. 5  A P P E N DI X 5: St a n d ar d C oc kcr oft a n d G a ult F or m ul a f or  C alc ul ate d Cre ati ni ne 
Cle ar a nce 
 
 
Sta n dar d C oc kcr oft a n d Ga ult F or m ula f or Calc ulate d Creati ni ne Cleara nce 
F or ser u m creati ni ne c o nce ntrati o n i n m g/ d L: 
Creati ni ne cleara nce ( Cr Cl) will be calc ulate d usi n g t he C oc kr oft- Ga ult e q uati o n as f oll o ws: 
  
( 1 4 0-a ge) X (act ual wei g ht i n k g) x 0. 8 5 f or fe males                                              
  
                                    7 2 x ser u m creati ni ne ( m g/ dl) 
 
 
F or ser u m creati ni ne c o nce ntrati o n i n 
m ol/ L: 
 
- 
 
Fe males: M ulti pl y t he res ult x 0. 8 5 
U nits: a ge i n years, wei g ht i n kil o gra ms. 
 
 
S o urce: C oc kcr oft D W, Ga ult M H. 1 9 7 6. Pre dic ti o n of creati ni ne cleara nce fr o m ser u m 
creati ni ne. 
Ne p hr o n 1 6: 3 1- 4.