Conditions: Non-small Cell Lung Cancer
Keywords: Carcinoma, Non-Small-Cell Lung
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is an open-label, single centre, Phase I study to determine the brain exposure of \[11C\]osimertinib in patients with EGFRm NSCLC with brain metastases.

Detailed description:
A Single-centre, Open-label, PET imaging and Pharmacokinetic Study of IV Administered \[11C\]osimertinib in EGFRm Non-small cell lung cancer patients with brain metastases. The study will consist of 2 phases, an imaging phase and a continuous access phase.

Arms:
arm 1: IV microdose administrations of \[11C\]osimertinib co-administered with 80 mg daily oral osimertinib.

Interventions: intervention 1: Osimertinib intervention 2: [11C]osimertinib
Intervention descriptions: intervention 1: Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam. intervention 2: Patients will receive 3 single IV microdose administrations of \[11C\]osimertinib and PET exams on: Day 1, Day 2 (or up to Day 8) and Day 29.

Protocol document:
Prot_000.pdf: 
 
This document contains confidential commercial information, disclosure of which is 
prohibited without providing advance notice to AstraZeneca and opportunity to object’ 
 
 
 
 
 
 
 
Clinical Study Protocol  
Drug Substance 
[11C]osimertinib, osimertinib 
Study Code 
D5160C00043 
Version 
2.0 
 
Date 
24 September 2019 
An Open-label Positron Emission Tomography (PET) Study to Determine 
Brain Exposure of Osimertinib after Intravenous Microdose Administration 
of [11C]osimertinib and Therapeutic Oral Doses of Osimertinib to Patients 
with EGFR Mutated Non-Small Cell Lung Cancer and Brain Metastases 
Sponsor:  AstraZeneca AB. 151 85 Sodertalje. Sweden 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
 
Version 2.0 
Date 24 September 2019 
2 
 
VERSION HISTORY 
Version 1.0, 15 January 2018 
INITIAL CREATION 
Version 2.0, 24 September 2019 
Changes of the protocol are summarized below: 
3.1 Inclusion criteria:  
• 
4.  Updated to combine the criteria of the EGFR mutation T790M and the assessment by 
local laboratory via tissue/cytology or in plasma. 
• 
5. Criteria removed and language incorporated into Inclusion criteria 4. 
• 
6. Clarified confirmation of BM as having at least one non-measurable and/or measurable 
brain lesion at baseline as per CNS RECIST 1.1 
• 
7. Removed the following statement: with no deterioration over the previous 2 weeks 
• 
7. Minimum life expectancy has been decreased from 12 weeks to 4 weeks to reflect the 
target population for the study more accurately. 
3.2 Exclusion Criteria: 
• 
3. Updated to exclude subjects that have had treatment with an EGFR-TKI within 10 days 
as opposed to 15 days, in order to avoid the risk of disease flare. 
• 
5. Updated to exclude subjects with a history of brain metastases that is/are in the same 
hemisphere as the current brain metastases. 
• 
Cardiac criteria assigned as exclusion criteria 7. All numbering of subsequent criteria re-
assigned accordingly. 
• 
7. Language in Cardiac criteria updated as per most recent project specific safety 
requirements. 
Table 1: 
• 
Day (window) for Clinical Visit 3 and PET3 has been updated to reflect the maximum 
window for the PET and RECIST assessments following repeat dosing.  Prior was 29 +/-7 
days =36 days dosing.  Updated to +25 (+/-4 days). 
• 
PK sampling times in footnote O updated from 1, 2, 4 and 6 hour(s) to 2, 4 and 7.5 hour(s). 
Table 4: 
Updated language in (cardiac section) as per project specific safety requirements. 
 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
 
Version 2.0 
Date 24 September 2019 
3 
 
6.8.4 QTc prolongation: 
Updated language to align with the potential for QT changes. 
8.5.4 PET imaging: 
Clarified that this pertains to modified CNS RECIST 1.1 criteria. 
9. 3 Study timetable and end of study: 
Section 9.3.1 added detailing study and site closure as per ICH GCP requirements. 
11 References: 
Project specific safety requirements added as a reference along with the most recent 
versions of AZD9291 and [11C]Osimertinib Investigator’s Brochures. 
Appendix C: 
Updated as per most recent project specific safety requirements. 
- Language updated throughout the document to ensure consistency that approximately 12 
patients will be enrolled in order to obtain at least 8 evaluable patients. 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
 
Version 2.0 
Date 24 September 2019 
5 
 
until, in the opinion of the Investigator, the patients are no longer deriving clinical benefit, or 
the patients stop taking osimertinib for any other reason.  No clinical data will be collected 
during this phase other than sudden death of unknown reason, serious adverse events that may 
be related to osimertinib, outcomes of pregnancy and IP dispensing/accountability. 
Patients not participating in the continued access phase or who discontinue treatment during 
the imaging phase will return to the clinic for follow-up assessments 30 days (±7 days) after 
their last administration of osimertinib in the imaging phase.  If the patient’s last 
administration of osimertinib is in the continued access phase, the patient should be contacted 
30 days after their last administration of osimertinib to follow up on any existing AEs/SAEs 
and monitor for new AEs/SAEs that may be related to the IP and record any sudden deaths of 
unknown cause. 
Objectives 
Primary Objective: 
Outcome Measure: 
To determine the brain exposure of 
[11C]osimertinib in tumour regions of interest, 
(brain metastases, including leptomeningeal 
metastases) in patients with non-small cell 
lung cancer after a single intravenous 
microdose and after single and multiple 
therapeutic administrations of osimertinib. 
The percent of injected dose in the whole brain and 
brain standard uptake value, to describe maximal 
radioactivity concentration in the brain. 
The time of the maximum radioactivity concentration 
in the brain. 
The brain to plasma partition coefficient 
(concentration brain/plasma ratio) as area under the 
concentration-time curve.  
All parameters of exposure will include the tumour 
region, whole brain and anatomical regions.  
 
Secondary Objective: 
Outcome Measure: 
To determine the pharmacokinetics of 
osimertinib and its metabolite (AZ5104) after 
multiple administrations of osimertinib. 
The following variables will be calculated where the 
data allow: maximum plasma concentration, time to 
reach maximum plasma concentration, area under the 
plasma concentration-time curve from zero to the last 
measurable time point. 
Also, the metabolite to parent ratio of the area under 
the plasma concentration-time curve and maximum 
concertation after a single administration will be 
calculated, as appropriate. 
 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
 
Version 2.0 
Date 24 September 2019 
7 
 
summarised for all patients who had post-administration pharmacokinetic assessments without 
any Clinical Study Protocol deviations or dosing deviations that might have affected the 
pharmacokinetic analysis.  Given the exploratory nature, no formal statistical analysis will be 
performed in this study.  The statistical analysis will be descriptive.  Demographic and 
baseline characteristics, imaging outcomes, safety outcomes, and treatment duration will be 
summarised using descriptive statistics, as appropriate.  


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CCI
CCI


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
9 
 
3.9.1 
Procedures for discontinuation of a patient from investigational product ............. 32 
3.10 
Criteria for withdrawal ........................................................................................... 33 
3.10.1 
Screen failures ........................................................................................................ 33 
3.10.2 
Withdrawal of the informed consent ...................................................................... 33 
3.11 
Discontinuation of the study .................................................................................. 34 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 34 
4.1 
Screening/Enrolment period .................................................................................. 37 
4.2 
Treatment period .................................................................................................... 38 
4.2.1 
Sequence of assessments ........................................................................................ 38 
4.3 
Continued access phase (CAP) .............................................................................. 39 
4.4 
Follow-up period .................................................................................................... 39 
5. 
STUDY ASSESSMENTS ..................................................................................... 40 
5.1 
Imaging assessments .............................................................................................. 40 
5.2 
Safety assessments ................................................................................................. 41 
5.2.1 
Laboratory safety assessments ............................................................................... 41 
5.2.2 
Physical examination ............................................................................................. 42 
5.2.3 
ECG ........................................................................................................................ 42 
5.2.4 
Echocardiogram/ MUGA scan ............................................................................... 43 
5.2.5 
Vital signs .............................................................................................................. 43 
5.3 
Other assessments .................................................................................................. 43 
5.3.1 
Ophthalmologic exam ............................................................................................ 43 
5.3.2 
Imaging assessments .............................................................................................. 44 
5.4 
Pharmacokinetics ................................................................................................... 45 
5.4.1 
Collection of PK samples ....................................................................................... 45 
5.4.2 
Determination of drug concentration ..................................................................... 45 
5.4.3 
Storage and destruction of PK samples.................................................................. 45 
5.5 
Pharmacodynamics (Not applicable) ..................................................................... 46 
5.6 
Genetics (Not Applicable) ..................................................................................... 46 
5.7 
Biomarker analysis ................................................................................................. 46 
5.7.1 
Collection of plasma and CSF samples ................................................................. 46 
5.7.2 
Storage, re-use and destruction of biological samples ........................................... 46 
5.7.3 
Labelling and shipment of biological samples ....................................................... 47 
5.7.4 
Chain of custody of biological samples ................................................................. 47 
5.7.5 
Withdrawal of Informed Consent for donated biological samples ........................ 47 
5.8 
Volume of blood .................................................................................................... 48 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 48 
6.1 
Definition of adverse events .................................................................................. 49 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
10 
 
6.2 
Definitions of serious adverse event ...................................................................... 49 
6.3 
Recording of adverse events .................................................................................. 49 
6.3.1 
Time period for collection of adverse events ......................................................... 49 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 49 
6.3.3 
Variables ................................................................................................................ 50 
6.3.4 
Causality collection ................................................................................................ 51 
6.3.5 
Adverse events based on signs and symptoms....................................................... 51 
6.3.6 
Adverse events based on examinations and tests ................................................... 51 
6.3.7 
Hy’s Law ................................................................................................................ 52 
6.3.8 
Disease progression ............................................................................................... 52 
6.3.9 
New cancers ........................................................................................................... 52 
6.3.10 
Handling of deaths ................................................................................................. 52 
6.4 
Reporting of serious adverse events....................................................................... 53 
6.5 
Overdose ................................................................................................................ 53 
6.6 
Pregnancy ............................................................................................................... 54 
6.6.1 
Maternal exposure .................................................................................................. 54 
6.6.2 
Paternal exposure ................................................................................................... 54 
6.7 
Medication error ..................................................................................................... 55 
6.8 
Management of IP related toxicities ...................................................................... 56 
6.8.1 
Skin reactions ......................................................................................................... 58 
6.8.2 
Diarrhoea ................................................................................................................ 58 
6.8.3 
ILD/Pneumonitis-like toxicity ............................................................................... 58 
6.8.4 
QTc prolongation ................................................................................................... 59 
6.8.5 
Keratitis and corneal ulceration ............................................................................. 59 
6.8.6 
Changes in cardiac contractility ............................................................................. 59 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 60 
7.1 
Identity of investigational product(s) ..................................................................... 60 
7.1.1 
Osimertinib ............................................................................................................ 60 
7.1.2 
[11C]osimertinib ..................................................................................................... 60 
7.2 
Dose and treatment regimens ................................................................................. 61 
7.3 
Labelling ................................................................................................................ 61 
7.4 
Storage ................................................................................................................... 62 
7.5 
Compliance ............................................................................................................ 62 
7.6 
Accountability ........................................................................................................ 62 
7.7 
Concomitant and other treatments ......................................................................... 63 
7.7.1 
Other concomitant treatment .................................................................................. 63 
7.8 
Post study access to study treatment ...................................................................... 63 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 64 


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CCI


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
12 
 
LIST OF TABLES 
Table 1 
Study Plan and timing of procedures ........................................................ 35 
Table 2 
Laboratory safety variables ...................................................................... 41 
Table 3 
Volume of blood to be drawn from each patient ...................................... 48 
Table 4 
Osimertinib dose adjustment information for adverse reactions .............. 57 
Table 5 
Dose interventions .................................................................................... 57 
Table 6 
Identity of investigational product ............................................................ 60 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 23 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 76 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................. 78 
Appendix C 
Guidance Regarding Potential Interactions with Concomitant 
Medications .............................................................................................. 79 
Appendix D 
Definition of Women of Childbearing Potential and Acceptable 
Contraceptive Methods. ............................................................................ 83 
Appendix E 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 85 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
13 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ABSS 
Automatic blood sampling system 
AE 
Adverse event (see definition in Section 6.1) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Absolute partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUCss 
Area under the concentration-time curve at steady state 
BBB 
Blood brain barrier 
BCRP 
Breast cancer resistance protein 
BP 
Blood pressure 
BM 
Brain metastases 
BMI 
Body mass index 
11C 
Carbon-eleven 
Cmax 
Maximum concentration after single dose 
Cssmax 
Maximum concentration at steady state 
CAP 
Continued access phase 
CNS 
Central nervous system 
CRF 
Case report form (paper) 
CSA 
Clinical study agreement 
CSF 
Cerebrospinal fluid 
CSP 
Clinical Study Protocol 
ctDNA 
Circulating tumour DNA 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DWI 
Diffusion-weighted imaging 
EC 
Ethics Committee 
ECHO 
Echocardiogram 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
14 
 
Abbreviation or 
special term 
Explanation 
ECG 
Electrocardiogram 
ED 
Effective dose 
EGFR 
Epidermal growth factor receptor 
EGFRm  
Epidermal growth factor receptor mutation positive 
EMA 
European Medicines Agency 
FSH 
Follicle-stimulating hormone  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus  
HRRT 
High resolution research tomograph 
HL 
Hy’s Law 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ILD 
Interstitial lung disease 
IP 
Investigational product 
IV 
Intravenous 
Kpu,u 
Brain/plasma partition coefficient 
LH 
Luteinising hormone 
LM 
Leptomeningeal metastases 
MBq 
Megabecquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition angiogram 
NSCLC 
Non-small cell lung cancer 
%ID 
Percent of radioactive drug injected 
PET 
Positron emission tomography 
PCV: 
Packed cell volume 
PHL 
Potential Hy’s law 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
15 
 
Abbreviation or 
special term 
Explanation 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected 
RECIST 
Response Evaluation Criteria In Solid Tumours 
ROI 
Region of interest 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event (see definition in Section 6.2) 
SD 
Standard deviation 
SUV 
Standardised uptake value 
SV 
Sievert 
TKI 
Tyrosine kinase inhibitor 
T790M 
Substituition of threonine to methionine at amino acid position 790 
Tmax 
Time of maximum drug concentration after single dose 
Tssmax 
Time of maximum drug concentration at steady state 
TT 
Thrombin time 
ULN 
Upper limit of normal 
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 
 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
16 
 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
1.1.1 
Non-small cell lung cancer and EGFR 
Lung cancer has been the most common cancer in the world for several decades, and by 2012, 
there were an estimated 1.8 million new cases, representing 12.9% of all new cancers.  It was 
also the most common cause of death from cancer, with 1.59 million deaths (19.4% of the 
total) (GLOBOCAN 2012).  Non-small cell lung cancer (NSCLC) represents approximately 
80% to 85% of all lung cancers.  Unfortunately, at the time of diagnosis approximately 70% 
of patients with NSCLC already have locally advanced or metastatic disease not amenable to 
surgical resection.  Furthermore, a significant percentage of patients with early stage NSCLC 
who have undergone surgery subsequently develop distant recurrence and die as a result of 
their lung cancer (Pisters and Le Chevalier 2005).  Patients presenting with unselected 
advanced NSCLC have a median overall survival of 10 to 12 months (Bonomi 2010). 
During the past decade, understanding the critical role of the epidermal growth factor receptor 
(EGFR) pathway and development of EGFR targeted tyrosine kinase inhibitors (TKI) have led 
to significant therapeutic advances in NSCLC.  Impressive anti-tumour activity was observed 
in a subset of patients, initially distinguished by their clinical, epidemiologic and histologic 
characteristics, and subsequently defined by the presence of activating mutations of EGFR 
(Lynch et al 2004).  The benefit of these TKIs in patients with EGFR mutations (EGFRm+) 
was initially demonstrated in the second-line and maintenance settings and subsequently 
confirmed in the first-line setting.  Such activating mutations are seen in 10% to 15% of 
NSCLC patients in the Western world and 30% to 40% in Asia.  As a result of first-line 
studies comparing a TKI versus chemotherapy in EGFRm+ patients (IRESSA Pan-Asia Study 
[IPASS] and EURopean TArceva versus Chemotherapy [EURTAC]), the National 
Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology 
(ESMO) currently recommend treatment with an EGFR-TKI (erlotinib, gefitinib, or afatinib) 
in the front-line setting for those patients with documented activating EGFRm+. 
In patients with sensitizing mutations of EGFR, response rates of 50% to 80% have been 
reported with first-line TKI treatment, compared with less than 30% with conventional 
chemotherapy.  Unfortunately, 50% to 60% patients ultimately develop acquired resistance to 
these agents (via substituition of threonine to methionine at amino acid position 790 mutation 
[T790M] for first and second generation EGFR-TKIs such as erolotinib, gefitinib and 
afatanib) with progression of disease after approximately 9 months to 13 months. 
Currently T790M that renders first-line TKI agents ineffective, is considered the primary 
cause of resistance to gefitinib, erlotinib or afatinib (this mutation accounts for approximately 
50% to 60% of cases of acquired resistance).  Osimertinib is currently approved by the Food 
and Drug Administration (FDA) and EMA (European Medicines Agency) for the treatment of 
patients who have progressed on a previous EGFR-TKI with EGFR T790M positive NSCLC 
and was recently granted Breakthrough Therapy Designation by the FDA as first-line 
treatment of EGFRm+ treatments for first-line EGFRm+ NSCLC, based on recent data 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
18 
 
1.1.4 
Osimertinib 
Osimertinib (TAGRISSO™) is a potent irreversible inhibitor of both the single EGFRm+ 
(TKI sensitivity conferring mutation) and dual EGFRm+/T790M+ (TKI resistance conferring 
mutation) receptor forms of EGFR.  Osimertinib has been shown to provide clinical benefit to 
patients with advanced NSCLC and both the single sensitizing mutations and the resistance 
mutation following prior therapy with an EGFR-TKI.  TAGRISSO™ (osimertinib) is 
currently approved in more than 65 countries including the US, EU, Japan and Korea for the 
treatment of adult patients with locally advanced or metastatic EGFR T790M mutation 
positive NSCLC. 
1.2 
Rationale for study design, doses and control groups 
Osimertinib has been shown to be active in treating patients with EGFRm+ NSCLC having 
pre-existing BM and/or has potential to slow down or prevent development of new BM.  
Preclinical studies in mice, rats and monkeys show that osimertinib crosses the intact BBB of 
animals and has good exposure in the brain regions of interest (ROIs).  It is hypothesized that 
the efficacy of osimertinib in the BM is because of its high BBB penetration in both normal 
and metastatic regions in the brain.  
The study will determine the distribution of [11C]osimertinib in the brain of patients with 
EGFRm+ NSCLC with BM.  It is hypothesized that the brain distribution of osimertinib is at 
least similar compared to the distribution in healthy subjects with an intact BBB (see 
Section 1.1.3) and it is at least similar at steady state compared to that observed after a single 
dose.  This evaluation of osimertinib BBB penetration in patients with NSCLC will support 
further use of osimertinib in other CNS mediated oncology indications.  The study design 
includes 2 phases for patients, the first (imaging) phase consisting of single IV microdose 
administrations of [11C]osimertinib and PET examinations on 3 occasions (baseline, post 
single dose and post repeat dose)  and the second phase consists of continued oral 
administrations of osimertinib.  
The study will test the following hypotheses: 
1. 
Osimertinib penetrates the BBB in patients with NSCLC and BM (including 
leptomeningeal metastases [LM]); whole brain exposure >1% injected dose. 
2. 
Whole brain and BM exposure of osimertinib at steady state is similar or higher 
compared to single dose. 
3. 
There may be changes in the size and number of BM at 3 weeks of treatment with 
osimertinib.   
4. 
Changes in the size and number of BM at 3 weeks correlate to the regional 
[11C]osimertinib exposure. 
5. 
Higher [11C]osimertinib levels in BM or LM reflect higher [11C]osimertinib 
exposure and/or binding to EGFR. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
19 
 
6. 
Exposure of osimertinib to BM region will be at least similar to that of the 
non-metastatic brain regions.  
Using high resolution PET examination, this open-label study will examine brain distribution 
and retention of a microdose of [11C]osimertinib in approximately 12 patients with EGFRm 
NSCLC and BM.  The imaging data analysis will include quantification of the maximum 
radioactivity concentration of [11C]osimertinib in the brain after injection (percent of injected 
dose entering the brain), but not limited to.  
After the imaging phase of the study patients will be allowed to continue to take osimertinib 
tablets (80 mg once daily) as a single agent in the continued access phase (CAP), depending 
on the agreement between the patient and Investigator.  Administration of osimertinib will 
continue until, in the opinion of the Investigator, the patients are no longer deriving clinical 
benefit, or the patients stop taking osimertinib for any other reason.  No clinical data will be 
collected during this phase other than sudden death of unknown reason, serious adverse events 
(SAEs) that may be related to osimertinib, outcomes of pregnancy and IP 
dispensing/accountability. 
Patients not participating in the CAP will return to the clinic for follow-up assessments 30 
days (±7 days) after their last dose of osimertinib in the imaging phase. If the patient’s last 
dose of osimertinib is during the CAP, the patient should be contacted 30 days after their last 
dose of osimertinib to follow up any existing SAEs and monitor for new SAEs that may be 
related to the investigational product (IP). 
1.3 
Benefit/risk and ethical assessment 
The patients with EGFRm (for definition of EGFR see Section 3.1) NSCLC enrolled in this 
study are likely to receive clinical benefit as osimertinib has shown clinical benefit in these 
patients across various studies.  Osimertinib demonstrates an acceptable benefit-risk profile in 
patients with NSCLC as evidenced by its approval from the regulatory agencies in more than 
65 countries including US, EU, Japan, Israel and South Korea.  Clinical tolerability data from 
patients indicate that osimertinib is generally well tolerated by patients with advanced cancer 
(please see to Section 1.3 of the AZD9291 Investigator’s Brochure 2019, Edition  for details).  
Inclusion and exclusion criteria as well as study restrictions are chosen to ensure the selected 
patients are exposed to minimal risk in this study. 
The current benefit/risk analysis is based on the available safety and tolerability data from 
studies in patients with NSCLC after multiple therapeutic doses of osimertinib.  
All studies of osimertinib exclude patients with clinically significant toxicities related to prior 
treatments in addition to specifically excluding patients with a history of interstitial lung 
disease (ILD) or clinically active ILD as this is an uncommon but well documented EGFR 
related toxicity.  All patients are assessed for known EGFR related toxicities and detailed 
information on the management of toxicities related to the IP is provided for all osimertinib 
studies (see Section 6.8).  All adverse events (AEs), vital signs, electrocardiograms (ECGs) 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
22 
 
Thorax/abdomen CT will be performed as routine clinical examination and will serve for the 
diagnosis and evaluation of primary lung tumour and other metastatic sites.  It will be repeated 
at the end of study treatment (on Day 25 ±4 days), to follow potential early effects on 
tumours. 
Positron emission tomography examination of the brain using [11C]osimertinib (administered 
before the start of PET) will be carried out 3 times: the first time at baseline (PET1; Visit 2 
[Day 1]), the second time after the first oral dose of osimertinib of 80 mg (PET2; Visit 3 
[Day 2], or within 1 week after baseline) and the third time after 3 weeks treatment with 
80 mg oral dose osimertinib daily (PET3; Visit 5 [Day 29]) (Figure 1B). 
At each PET examination [11C]osimertinib will be given IV as a microdose (<10 μg), at a 
radioactivity of 300 MBq/70 kg of body weight.  The minimum injected radioactivity will be 
200 MBq/70 kg of body weight and the maximum injected radioactivity will be 330 MBq/70 kg 
of body weight.  Brain radioactivity will be measured for 90 minutes (minimum 60 minutes) in 
the PET examination system (high resolution research tomograph [HRRT]).  
The PET2 examination and the PET3 examination will be performed on Visit 3 and Visit 5 
after IV [11C]osimertinib administration.  The IV dose will be given ~6 hours after the oral 
osimertinib 80 mg to coincide with the median time of maximum drug concentration (Tmax) of 
the oral dose.  All participants will receive at least 3 weeks (21 days) treatment with 80 mg 
oral dose of osimertinib once daily between the PET2 examination and PET3 examination 
visits.  
On completion of the imaging phase (ie, at the PET3 examination), patients may continue to 
take osimertinib tablets (80 mg once daily) as a single agent in the CAP depending on 
agreement between the patient and the Investigator.  This will continue until, in the opinion of 
the Investigator, the patients are no longer deriving clinical benefit, or the patients stop taking 
osimertinib for any other reason.  No clinical data will be collected during this phase other 
than sudden death of unknown reason, SAEs that may or may not be related to osimertinib, 
outcomes of pregnancy and IP dispensing/accountability (Figure 1).   
Dose reduction of osimertinib (to 40 mg once daily) according to clinical practise will be 
allowed in the CAP if deemed necessary by the Investigator due to AEs.  
Patients not participating in the CAP or who discontinue treatment during the imaging phase 
will return to the clinic for follow-up assessments 30 days (±7 days) after their last dose of 
osimertinib in the imaging phase.  If the patient’s last dose of osimertinib is in the CAP, the 
patient should be contacted 30 days after their last dose of osimertinib to follow up any 
existing SAEs and monitor for new SAEs that may be related to the IP, and record any sudden 
deaths of unknown cause. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
23 
 
Figure 1 
Study flow chart 
 
C: PET examination flow 
 
= Tablet dosing 
CT: Computed tomography; IV: Intravenous; MRI: Magnetic resonance imaging; PET: Positron emission 
tomography.
 
A: Study flow   
 
 
 
 
 
 
 
B: Study period (drug administration and imaging measurements) 
 
                                     
                          up  
 
 
 
 
PET-1  
PET 
measurement 
using IV 
[11C]osimertinib  
PET-2  
PET using IV 
[11C]osimertinib,  
after single 80 mg 
oral dose of 
osimertinib  
PET-3  
PET using IV 
[11C]osimertinib,  
after 80 mg oral dose 
of osimertinib 
MRI-2 
CT-2 
Osimertinib 
80 mg, oral once 
daily 
Drug continuation phase 
Continued treatment 
Continuing access to 
treatment as by 
individual patients needs 
 
Screening 
Enrolled subjects  
(incl MRI, CT) 
n=appr .12 
Day -28 to Day -1 
Visit 1-2 
Administration of osimertinib 
Imaging measurements 
(PET, MRI, CT) 
n=8 
Day -1 to Day 39 
Visit 2-6 
Screening period 
Study period (Imaging phase) 
PET image  
data analysis 
PET image  
data analysis 
PET image data 
analysis 
Up to  
1 week 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
24 
 
1.5 
Study governance and oversight 
No Data Monitoring Committee is planned, as this study is an open-label non-randomised 
Phase I study.  In addition the safety profile of osimertinib in a similar NSCLC patient 
population is well established and predictable.  Therefore, there is no requirement for pre-
planned specified expert independent safety reviews in this study. 
Safety data will be reviewed on an ongoing basis by the internal AstraZeneca and delegated 
Contract Research Organisation (CRO) study team as appropriate.  The internal study team 
will evaluate progress of the study, assess safety and other relevant information for the study, 
and will make decisions on continuation, modification or discontinuation of the study. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To determine the brain exposure of 
[11C]osimertinib in tumour ROI (BM, 
including LM) in patients with NSCLC after a 
single IV microdose and after single and 
multiple therapeutic doses of osimertinib.   
The percent of injected dose in the whole brain (%ID) 
and brain standard uptake value (SUV), to describe 
maximal radioactivity concentration in the brain, 
(Cmax, %ID brain; Cmax, SUVbrain).  
The time of the maximum radioactivity concentration 
in the brain (Tmax brain). 
The brain to plasma partition coefficient 
(concentration brain/plasma ratio) as area under the 
concentration curve (AUC)brain 0-90min/AUCblood 0-90min. 
All parameters of exposure will include the tumour 
region, whole brain and anatomical regions. 
AUC: Area under the concentration curve; BM: Brain metastases; Cmax: Maximum concentration after single 
dose; IV: Intravenous; LM: Leptomeningeal metastases; NSCLC: Non-small cell lung cancer; ROI: Region of 
interest; Tmax: Time of maximum drug concentration after single dose. 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
To determine the PK of osimertinib and its 
metabolite (AZ5104) after multiple 
administrations of osimertinib. 
The following variables will be calculated where the 
data allow: maximum plasma concentration (Cssmax), 
time to reach maximum plasma concentration (tssmax), 
area under the plasma concentration-time curve from 
zero to the last measureable time point (AUCss). 
Also, the metabolite to parent ratio of the AUC and 
maximum concentration after single dose (Cmax) will 
be calculated, as appropriate. 
AUC: Area under the concentration curve; Cmax: Maximum concentration after single dose; PK: Pharmacokinetics 


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CCI


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
26 
 
3. 
PATIENT SELECTION, ENROLMENT, 
RANDOMISATION, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.  
3.1 
Inclusion criteria 
For inclusion in the study patients must fulfil the following criteria: 
1. 
Provision of signed and dated, written informed consent prior to any study specific 
procedures, sampling and analyses.  Procedures performed for routine clinical 
practice up to 2 weeks before the provision of written consent are acceptable if not 
intentionally done for study purposes. 
If a patient declines to participate in any voluntary exploratory research and/or 
genetic component of the study, there will be no penalty or loss of benefit to the 
patient and he/she will not be excluded from other aspects of the study. 
2. 
Male or female aged at least 18 years. 
3. 
Histological or cytological confirmation of diagnosis of NSCLC.  
4. 
Confirmation that the tumour harbours an EGFR mutation known to be associated 
with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or 
T790M EGFR resistance mutation as assessed by local laboratory/or central 
laboratory via tissue/cytology or in plasma. 
5. 
Mandatory provision (if available) of formalin fixed, paraffin embedded tissue and 
blood for central confirmation of EGFR mutation status. Please refer to the 
Laboratory Manual for details. 
6. 
In all patients enrolled, confirmed BM as having at least one non-measurable and/or 
measurable brain lesion at baseline as per CNS RECIST 1.1 via MRI imaging.  
7. 
World Health Organisation (WHO) performance status 0 to 2 and a minimum life 
expectancy of 4 weeks. 
8. 
Females should be using adequate contraceptive measures (up to 6 months after the 
last administration; see restriction section), should not be breastfeeding and must 
have a negative serum pregnancy test prior to start of dosing if of childbearing 
potential or must have evidence of non-childbearing potential by fulfilling 1 of the 
following criteria at screening: 
• 
Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments.  


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
27 
 
• 
Women under 50 years old would be consider postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and with luteinising hormone (LH) and follicle-stimulating hormone 
(FSH) levels in the post-menopausal range for the institution.  
• 
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.  
9. 
Male subjects should be willing to use barrier contraception (see Restrictions, 
Section 3.8). 
10. 
Have a body mass index (BMI) between 18.0 kg/m2 and 30.0 kg/m2 inclusive and 
weigh at least 40.0 kg and no more than 100.0 kg, inclusive 
11. 
Able and willing to participate in all scheduled evaluations, abide by all study 
restrictions, and complete all required tests and procedures. 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study centre). 
2. 
Participation in another clinical study with an IP during the previous 14 days (or a 
longer period, depending on the defined characteristics of the agents used).  
3. 
Treatment with any of the following: 
• 
Treatment with an EGFR-TKI (erlotinib, gefitinib or afatinib) within 10 days or at 
least 5x the half-life, whichever is the longer, of the first administration of IP.  If 
sufficient washout time has not occurred due to schedule or PK properties, an 
alternative appropriate washout time based on known duration and time to 
reversibility of IP related AEs could be agreed upon by AstraZeneca and the 
Investigator. 
• 
Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from 
a previous treatment regimen or clinical study within 14 days of the first 
administration of the IP. 
• 
Osimertinib in the present study (ie, administration with osimertinib previously 
initiated in this study) or other studies.  Patients who were enrolled, screened but 
not dosed (ie, withdrew from the study prior to dosing) may be re-enrolled and 
rescreened if in the opinion of the Investigator, the reason(s) for earlier withdrawal 
no longer applies. 
• 
Major surgery (excluding placement of vascular access) within 4 weeks of the first 
administration of the IP. 
• 
Radiotherapy (including brain) with a limited field of radiation within 1 week of the 
first administration of the IP, with the exception of patients receiving radiation to 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
28 
 
more than 30% of the bone marrow or with a wide field of radiation which must be 
completed within 4 weeks of the first administration of the IP. 
• 
Patients currently receiving (or unable to stop use at least 3 weeks before receiving 
the first administration of osimertinib) medications or herbal supplements known to 
be potent inducers of CYP3A4 (see Appendix B). 
4. 
Any unresolved toxicities from prior therapy greater than the Common 
Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting 
the IP with the exception of alopecia and grade 2, prior platinum therapy-related 
neuropathy. 
5. 
History of brain surgery or major brain trauma in the last year (if the surgery is in 
the same hemisphere as the brain metastasis).  
6. 
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled 
hypertension and active bleeding diatheses, which in the Investigator’s opinion 
makes it undesirable for the patient to participate in the study or which would 
jeopardise compliance with the CSP, or active infection including hepatitis B, 
hepatitis C and human immunodeficiency virus (HIV).  Screening for chronic 
conditions is not required (hepatic impairment is excluded from this criterion). 
7. 
Any of the following cardiac criteria: 
− 
Mean resting corrected QT interval (QTc) >470 msec obtained from 3 ECGs, 
using the screening clinic ECG machine derived QTc value. 
− 
Any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG (eg, complete left bundle branch block, third degree heart block, 
second degree heart block). 
− 
Patient with any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as electrolyte abnormalities including:  
− 
⁃ Serum/plasma potassium <lower limit of normal (LLN)  
− 
⁃ Serum/plasma magnesium <lower limit normal (LLN) 
− 
 ⁃ Serum/plasma calcium <lower limit normal (LLN)  
       heart failure, 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 and 
cause Torsades de Pointes.  
 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
29 
 
8. 
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which 
required steroid treatment, or any evidence of clinically active ILD. 
9. 
Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values: 
• 
Absolute neutrophil count <1.5 × 109/L  
• 
Platelet count <100 × 109/L 
• 
Haemoglobin <90 g/L 
• 
Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no 
demonstrable liver metastases or >5 times ULN in the presence of liver metastases.  
• 
Aspartate aminotransferase (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 liver metastases or Gilbert’s Syndrome. 
• 
Creatinine >1.5 times institutional ULN concurrent with creatinine clearance 
<50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation of 
creatinine clearance is only required when creatinine is >1.5 times institutional 
ULN. 
10. 
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. 
11. 
History of hypersensitivity to active or inactive excipients of osimertinib or drugs 
with a similar chemical structure or class to osimertinib. 
12. 
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements. 
13. 
In addition, the following is considered a criterion for exclusion from the 
exploratory genetic research: 
• 
Previous allogenic bone marrow transplant 
• 
Non-leukocyte depleted whole blood transfusion within 120 days of the date of the 
genetic sample collection 
14. 
Patients on anticoagulant treatment. 
15. 
Absence of collateral flow between ulnar and radial artery as assessed by the 
Allen´s test” to avoid misunderstandings. 
16. 
Suffering from claustrophobia and/or having implanted metal devices or implants 
such as pacemaker, vascular or heart valves, stents, clips, also metal deposits such 
as bullets, shells, metal grains in the eyes. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
30 
 
17. 
Previous participation in a research PET or PET/CT study. 
18. 
The following are exclusion criteria for contrast enhanced MRIs:  
• 
Glomerular filtration rate <30 ml/min 
• 
History of renal insufficiency 
• 
Pregnancy 
19. 
Women who are breast-feeding. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrolment  
The Investigator should keep a record, the patient screening log, of patient’s who entered 
pre-study screening. 
The Principal Investigator (PI) or designee will: 
1. 
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
2. 
Assign potential patients a unique enrolment code (E-code) beginning with ‘E#’ 
after written informed consent has been obtained.  The E-code (EWWXXYZZ) will 
consist of a 2-digit country number (WW), a 2-digit site number (XX), a 1-digit 
study number (Y) and a 2-digit patient number (ZZ, starting with 01) issued by the 
study centre in order of informed consent taken. 
3. 
Determine patient’s eligibility. See Section 3.1 and 3.2. 
If a patient withdraws from participation in the study, then his/her enrolment code cannot be 
reused. 
Patients who were enrolled, screened but not administered the IP (ie, withdrew from the study 
prior to administration) may be re-enrolled and re-screened if, in the opinion of the 
Investigator, the reason(s) for earlier withdrawal no longer applies.  A new enrolment code 
will be assigned to these patients.  Patients cannot re-enter the study if the IP was administered 
and subsequently withdrawn from the study.  Patients who discontinue their participation in 
the imaging phase prematurely may still be eligible to continue to take osimertinib in the 
CAP, if the Investigator believes it is in the patient’s interest, ie, discontinuation from the 
imaging phase may not necessarily result in withdrawal from the study. 
3.4 
Procedures for handling incorrectly enrolled patients 
Patients who fail to meet the eligibility criteria should not be enrolled or receive IP under any 
circumstances.  There can be no exceptions to this rule. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
31 
 
Where patients who do not meet the selection criteria are enrolled in error or incorrectly 
started on treatment, or where patients subsequently fail to meet the study criteria 
post-initiation, a discussion should occur between the AstraZeneca Physician or his/her 
representative and the Investigator regarding whether to continue or discontinue the patient 
from treatment.  Once a decision is made, Investigators need to ensure that they comply with 
all applicable requirements for human patient protection and ethical review. 
The AstraZeneca Physician or his/her representative is to ensure all such decisions are 
appropriately documented.  In situations where an agreement cannot be reached, the patient 
should have their study treatment stopped and be withdrawn from the study. 
3.5 
Methods for assigning treatment groups (Not applicable) 
3.6 
Methods for ensuring blinding (Not applicable) 
3.7 
Methods for unblinding (Not applicable) 
3.8 
Restrictions 
The following restrictions apply while the patient is receiving the IP and for the specified 
times before and after: 
1. 
Females of child-bearing potential should use reliable methods of contraception 
from the time of screening until 6 weeks after discontinuing study treatment.  
Acceptable methods are provided in Appendix C (Definition of Women of 
Childbearing Potential and Acceptable Contraceptive Methods).  
2. 
Male patients should be asked to use barrier contraceptives (ie, by use of condoms) 
during sex with all partners during the trial and for a washout period of 4 months.  
Male patients should avoid procreation for 4 months after completion of trial 
treatment.  Patients should refrain from donating sperm from the start of dosing 
until 4 months after discontinuing study treatment.  
3. 
Once enrolled all patients must try to avoid concomitant use of medications, herbal 
supplements and/or ingestion of foods that are known to be potent inducers of 
CYP3A4 whenever feasible, but patients may receive any medication that is 
clinically indicated for treatment of AE.  Such drugs must have been discontinued 
for an appropriate period before they enter screening and for a period of 3 months 
after the last administration of osimertinib.  All concomitant medications should be 
captured on the paper case report form (pCRF).  Guidance on medicines to avoid, 
medications that require close monitoring and on washout periods is provided (see 
Appendix B “Guidance regarding Potential Interactions with Concomitant 
Medications”). 
4. 
If medically feasible, patients taking regular medication, with the exception of 
strong inducers of CYP3A4 (see Appendix B), should be maintained on their 
regular medication throughout the study period. Patients taking concomitant 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
32 
 
medications whose disposition is dependent upon the Breast Cancer Resistance 
Protein (BCRP) and/or P-glycoprotein (P-gp) with a narrow therapeutic index 
should be closely monitored for signs of changed tolerability as a result of increased 
exposure of the concomitant medication whilst receiving Osimertinib. Guidance on 
medications to avoid, medications that require close monitoring and on washout 
periods is provided (see Appendix B “Guidance regarding Potential Interactions 
with Concomitant Medications”). 
5. 
Patients taking rosuvastatin should have creatine phosphokinase levels monitored 
(due to BCRP-mediated increase in exposure).  If the patient experiences any 
potentially relevant AEs suggestive of muscle toxicity including unexplained 
muscle pain, tenderness, or weakness, particularly if accompanied by malaise or 
fever, rosuvastatin must be stopped and any appropriate further management should 
be taken. 
6. 
Refrain from hard physical training (such as heavy lifting) for a period of 7 days 
following arterial catheterisation. 
3.9 
Discontinuation of investigational product 
Patients may be discontinued from IP in the following situations: 
• 
Patient decision.  At any time the patient is free to discontinue treatment, without 
prejudice to further treatment 
• 
AE 
• 
Severe non-compliance with the CSP 
• 
Disease progression and/or the Investigator believes they are no longer deriving 
clinical benefit 
• 
Incorrectly enrolled patients 
• 
Corneal ulceration 
• 
ILD/pneumonitis 
• 
QTc interval prolongation with signs/symptoms of serious arrhythmia 
3.9.1 
Procedures for discontinuation of a patient from investigational product  
A patient who decides to discontinue the IP will always be asked about the reason(s) and the 
presence of any AEs.  If possible, they will be seen and assessed by an Investigator.  Adverse 
events will be followed up (See Section 6.3.2); and all IP should be returned by the patients. 
In the imaging phase, any patient discontinuing the IP should be seen at 30 days (±7 days) 
after their last administration for the evaluations outlined in the Study Plan (see Table 1).  
After discontinuation of the IP, the Investigator will perform the best possible observations, 
tests and evaluations, as well as give appropriate medication and ensure all possible measures 
for the safety of the patient. 
After discontinuation of the IP in the imaging phase, all ongoing AEs or SAEs must be 
followed until resolution unless, in the Investigator’s opinion, the condition is unlikely to 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
33 
 
resolve due to the patient’s underlying disease, or the patient is lost to follow up (see 
Section 6).  All new AEs and SAEs occurring during the 30 calendar days after the last 
administration of IP or immediately before initiation of any other cancer therapy, whichever 
occurs first, must be reported (all SAEs must be reported to AstraZeneca or its representative 
within 24 hours as described in Section 6.4) and followed to resolution as above.  Patients 
should be contacted at least 30 days after discontinuing IP to complete AE information and/or 
collect IP.  Any untoward event occurring subsequent to the 30 day AE reporting follow-up 
period that the Investigator assesses as possibly related to the IP should also be reported as an 
AE. 
At the end of the imaging phase, patients may continue to receive the IP as continued access 
and undergo follow-up as part of their normal routine clinical care.  After discontinuation of 
the IP in continued access, patients should be followed for 30 days to follow-up any existing 
SAEs and monitor for any new SAEs that may be related to the IP. 
If a patient is withdrawn from study, see Section 3.10. 
3.10 
Criteria for withdrawal  
Patients will be withdrawn from the study for the following reasons: 
• 
Screen failures (see Section 3.10.1) 
• 
Voluntary withdrawal by the patient who is any time free to discontinue their 
participation in the study, without prejudice to further treatment (see Section 3.10.2) 
• 
Risk to patients as judged by the Investigator and/or AstraZeneca or its 
representative 
• 
Severe non-compliance to the CSP as judged by the Investigator and/or 
AstraZeneca or its representative 
• 
Incorrectly enrolled patients, ie, the patient does not meet the required 
inclusion/exclusion criteria for the study 
• 
Patient becomes pregnant 
• 
Patient lost to follow-up 
3.10.1 
Screen failures  
Screen failures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be dosed.  These patients should have the reason for study withdrawal recorded as 
‘Eligibility Criteria Not Fulfilled’ (ie, patient does not meet the required inclusion criteria or 
meets an exclusion criterion).  This reason for study withdrawal is only valid for screen 
failures (not dosed patients). 
3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment (withdrawal of consent).  Patients may withdraw from any 
aspects of the optional genetics research (see Section 3.1 and Section 5.6) at any time, without 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
34 
 
prejudice to further treatment and independent of any decision concerning participation in 
other aspects of the main study. 
If a patient wishes to withdraw their consent to further participation in the study entirely this 
should be clearly documented in the patient notes and in the clinical study database.  Patients 
will always be asked about the reasons for withdrawal of consent for and the presence of any 
AEs.  The Investigator will follow up AEs outside the clinical study. 
If a patient withdraws from participation in the study, then his/her E-code cannot be reused. 
3.11 
Discontinuation of the study 
The study will be stopped if, in the judgement of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings that: 
• 
Meet individual stopping criteria or are otherwise considered significant 
• 
Are assessed as causally related to the IP 
• 
Are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the pCRF.  All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES  
The overall Study Plan is provided in Table 1 for the imaging phase. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
35 
 
Table 1 
Study Plan and timing of procedures 
Activity 
 
Screening 
period 
Study period 
Follow
up 
PET1 
PET2 
Clinical 
Visit 2 
Clinical 
Visit 3 
and PET3 
MRI2 
Visita  
1a,b 
2 
3c 
4d 
5e 
6 
7w,x 
Day (window) 
-28 to -1 
day before 
dosing 
1 
2 
(within 
6 days) 
14 (±2 
days) 
+25 (±4 
days) 
 
 
Obtain informed consent 
and/or consent for 
pharmacogenetics 
X 
 
 
 
 
 
 
Confirm eligibility  
X 
 
 
 
 
 
 
Demographics & 
baseline characteristics 
Xb 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
Relevant medical and 
surgical history 
(including smoking 
status) 
X 
 
 
 
 
 
 
Ophthalmic 
examinationf 
X 
 
 
 
 
 
 
WHO performance 
status 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
X 
X 
 
X 
Brain MRI 
Xg, h 
 
 
 
Xh 
Xh 
 
Allen’s testi 
X 
X 
X 
 
X 
 
 
Thorax/abdomen CT 
X 
 
 
 
 
Xe 
 
Resting standard 12-lead 
ECG 
Xb 
X 
X 
X 
X 
 
 
Echcardiography 
(ECHO/MUGAj) 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
HBV, HCV and HIV 
serology 
X 
 
 
 
 
 
 
Weight and height  
Xk 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
X 
Laboratory tests 
(haematology, clinical 
chemistry, coagulation)l 
X 
X 
X 
X 
X 
 
X 
Urine analysisl 
X 
X 
X 
X 
X 
 
 
Serum or urine 
pregnancy testm (LH, 
FSH) 
X 
X 
X 
X 
X 
 
X 
Review current 
medications 
Xn 
Xn 
Xn 
Xn 
Xn 
 
X 
Blood sampling for 
osimertinib PK 
 
 
Xo 
 
Xo 
 
 
CSFp  
X 
 
 
 
X 
 
 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
36 
 
Table 1 
Study Plan and timing of procedures 
Activity 
 
Screening 
period 
Study period 
Follow
up 
PET1 
PET2 
Clinical 
Visit 2 
Clinical 
Visit 3 
and PET3 
MRI2 
Visita  
1a,b 
2 
3c 
4d 
5e 
6 
7w,x 
Day (window) 
-28 to -1 
day before 
dosing 
1 
2 
(within 
6 days) 
14 (±2 
days) 
+25 (±4 
days) 
 
 
Tissue and blood 
sampling for EGFR 
mutations/resistance 
mechanismsq 
Xq 
 
 
 
 
 
Xq 
Blood sampling for 
ctDNA/exosomal 
DNA/RNA/protein 
X 
X 
X 
 
X 
 
X 
Arterial catheter 
placementr, and arterial 
blood sampling for 
[11C]osimertinibs  
 
X 
X 
 
X 
 
 
Venous blood sampling 
for [11C]osimertinib 
radioactivity and 
metabolitesr,t 
 
X 
X 
 
X 
 
 
[11C]osimertinib 
administration 
 
X 
X 
 
X 
 
 
PET examination 
 
Xe,t 
Xe,t 
 
Xe,t 
 
 
Osimertinib oral 
administration 80mg 
once dailyu 
 
 
X (continuous daily administration)  
 
Adverse event review 
(AEs and SAEs) 
Xv 
Xv 
Xv 
Xv 
Xv 
 
Xv,w,x 
AE: Adverse event; BM:Brain metastases; CSF: Cerebrospinal fluid; CT: Computed tomography; ctDNA: Circulating tumour 
DNA; ECHO: Echocardiogram DNA: Deoxyribonucleic acid; ECG: Electriocardiogram; EGFR: Epidermal growth factor 
receptor; FSH: Follicle-stimulating hormone; HBV: Hepatitis B virus, HCV: Hepatitis C virus; HIV: Human 
immunodeficiency virus; IP: Investigational product; IV; Intravenous; MRI: Magnetic resonance imaging; 
MUGA: Multigated radionuclide angiogram; LH: Luteinising hormone; PET: Positron emission tomography; 
PK: Pharmakonitetics; RNA: Ribonucleic acid; SAE: Serious adverse event; WHO: World Heatlh Organisation. 
a  
Study procedures designated for a specific visit should be performed in 1 day whenever possible and in the best interest 
of the patient.  If this is not possible and/or not in the best interest of the patient, study procedures may be performed 
across more than 1 day, but within the visit window. 
b 
Day -1 is the day before dosing. All Day 1 procedures must be performed on Day -1 or pre-administration on Day 1 
provided the results are reviewed before dosing.  If the patient has been screened within 48 hours of Day 1, safety 
laboratory tests (haematology, coagulation, biochemistry and urine analysis) do not need to be repeated. 
c  
PET2 can be conducted on Day 2 (1 day after the PET1 or within the 1 week of PET1 ie, 1 to 6 days of [11C]osimertinib 
washout is allowed).  
d  
A clinical visit will be scheduled for when the patient has been on the continuous IP administration for 10 days 
(window of ±2 days).  
e  
The clinical visit for the PET3 examination and CT-2, MRI-2 can be conducted on the same day or on a different day.  
If the assessmnets cannot be conducted on the same day, the CT-2, MRI-2 can be conducted within a window of 7 days.  
f 
Full ophthalmic assessment, including slit lamp examination, will be performed at screening and if a patient experiences 
any visual symptoms (including blurring of vision), with additional tests, if clinically indicated.  Photographs will be 
taken to record any clinically significant findings.   
g 
Brain MRI should confirm presence of BM. 


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CCI


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
38 
 
Patients will be considered to be in the screening period until all Visit 1 assessments are 
completed and eligibility is confirmed.  Patients will be considered to be in the treatment 
period after the first PET examination with [11C]osimertinib. 
The following assessments and procedures should be performed within 28 days prior to the 
first administration of the IP: 
• 
Signed informed consent for the study and pharmacogenetics informed consent 
(optional). 
• 
Review inclusion/exclusion criteria; ensure that patient has documented an EGFRm 
(local testing conducted at an accredited laboratory) known to be associated with 
EGFR-TKI sensitivity (eg, G719X, exon 19 deletion, L858R, L861Q) and a T790M 
mutation in EGFR if previously treated with EGFR-TKI. 
• 
Demographics (sex, age, self-reported race/ethnicity). 
• 
Medical/surgical history including smoking status. 
• 
Prior and concomitant medications including prescribed and over-the-counter 
preparations and previous cancer therapies (if applicable), check against exclusion 
criteria, restrictions (see Section 7.7) and Appendix B. 
• 
Physical examination, WHO performance status, vital signs (supine BP and pulse, 
body temperature), ECG, echocardiogram (ECHO) or multiple gated acquisition 
scan (MUGA) for left ventricular ejection fraction (LVEF), body weight and height 
• 
Haematology, clinical chemistry and coagulation, serology (hepatitis B and 
hepatitis C status) and urine analysis. 
• 
Serum or urine pregnancy test (pre-menopausal women of childbearing potential). 
• 
Ophthalmology: Full ophthalmic assessment, including slit lamp examination, 
should be performed at screening and if a patient experiences any visual symptoms 
(including blurring of vision), with additional tests if clinically indicated.  
Ophthalmology examination results should be collected in the pCRF.  Any 
clinically significant findings, including those confirmed by the ophthalmologist 
must be reported as an AE.  Photographs should be performed to record any 
clinically significant findings.  These photographs should be available for central 
review by AstraZeneca and AstraZeneca representatives if necessary.  Patients 
experiencing corneal ulceration will not be permitted to restart the IP. 
• 
AEs 
4.2 
Treatment period 
Descriptions of the procedures for this period are included in the Study Plan with exceptions 
of the following specific requirements for the treatment period. 
4.2.1 
Sequence of assessments 
It is important that arterial and venous sampling occurs as close as possible to the scheduled 
time.  In order to achieve this, other assessments scheduled at the same time may be initiated 
prior to the time point.  The sequence to be followed at a particular post-administration time 
point is: 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
39 
 
1. 
ECGs 
2. 
Vital signs 
3. 
Blood sample (at scheduled time) 
4. 
Any other measurements 
Before the first administration of [11C]osimertinib, pre-administration ECGs and vital signs 
should be collected within 60 minutes prior to administration.  All Day -1 procedures in the 
imaging phase must be performed in the clinic on Day -1 or pre-administration on Day 1; 
patients may be admitted on Day 1 if the Day -1 activities (see Table 1) can be completed on 
the same day.  If the patient has been screened within 48 hours of Day 1, safety laboratory 
tests (haematology, coagulation, clinical chemistry and urine analysis) do not need to be 
repeated. 
4.3 
Continued access phase (CAP) 
During the CAP osimertinib can be taken with or without food.  Following completion of the 
imaging phase, patients may continue to take osimertinib as a single agent, if they and the 
Investigator deem it appropriate, until such time as the Investigator believes they are no longer 
deriving clinical benefit or they stop taking osimertinib for any other reason. Patients will be 
seen as per their normal routine clinical schedule.  No clinical data will be collected during 
this phase other than sudden death of unknown reason, SAEs that may be related to 
osimertinib, outcomes of pregnancy and IP dispensing/accountability.  
4.4 
Follow-up period 
Descriptions of the procedures for this period are included in the Study Plan with exceptions 
of the following specific requirements for the follow-up period:  
Those patients who do not proceed into CAP will return to the clinic for follow-up 
assessments 30 days (±7 days) after their last administration in the imaging phase; follow-up 
assessments are detailed in Table 1. 
If the patient’s last administration of osimertinib is in the CAP (ie, after the imaging phase), 
the patient should be contacted 30 days after their last administration of osimertinib to follow 
up on any existing SAEs and monitor for new SAEs that may be related to IP. 
A post-study assessment will be performed 7 working days after the last [11C]osimertinib has 
been infused and the PET examination is completed.  In the event of a holiday or weather 
delay the follow-up call may be postponed 1 to 2 working days.  If the patient can not be 
contacted within 14 days as scheduled, the Investigator designee/centre staff must try again.   
The patient will be asked about any symptoms or ill-effects since the time of the procedure.  
The patient will also be reminded to: 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
40 
 
• 
Contact the Investigator or designee at the PET centre, if within the follow-up 
period following participation in the study, they feel ill effects related to the study. 
The post study follow-up call and outcome will be recorded in the patient’s medical record. 
5. 
STUDY ASSESSMENTS 
The In Form Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The Investigator will ensure that data are recorded on the pCRF as specified 
in the CSP and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The Investigator will sign the completed pCRFs.  A copy of the completed pCRFs will be 
archived at the study centre.  
5.1 
Imaging assessments 
The following study assessments will be obtained.  The timings of these assessments are 
detailed in the Study Plan (Table 1). 
• 
MRI assessment 
Patients will undergo a pre-scan check prior to an MRI scan of the brain.  Patients will be 
asked to lie on their back in the MRI scanner where a head coil will be placed over the head 
and shoulders.  During the scan, the patients will undergo an IV injection of gadolinium 
contrast agent.  The scans will be used for BM assessments by CNS RECISTv1.1 (Eisenhauer 
et al 2009) delineation of brain lesions regions for corresponding PET analysis and to examine 
BBB breakdown. 
• 
Thorax/Abdomen CT 
Patients will undergo a thorax/abdomen CT scan, including chest and abdomen and pelvis if 
there is disease present.  The scans will be used for extra-cranial tumour assessments 
according to RECSIT v1.1.  Additional CT scans, including neck region, may be included 
depending on metastasis location. 
• 
PET examinations 
Brain PET examination procedures will include IV administration of [11C]osimertinib 
followed by brain radioactivity measurements using the HRRT PET system and radioactivity 
measurements in blood (arterial and venous) (for detailed description see Section 5.3.2.2). 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
41 
 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, and urine 
analysis will be taken during Visit 1 as indicated in the Study Plan.   
The date and time of each collection will be recorded in the appropriate pCRF. 
Following a review of data from a group of patients, the timing of blood samples may be 
adjusted for subsequent groups of patient.   
The following laboratory variables will be measured: 
Table 2 
Laboratory safety variables 
Clinical chemistry (2.7 mL sample) 
Haematology (2.7 mL sample) 
S/P-Albumin 
B-Hb 
S/P-ALT 
B-Leukocyte 
S/P-AST 
B-Absolute leukocyte differential count: 
neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
S/P-Alkaline phosphatase 
B-Platelet count   
S/P-Bilirubin, total 
B-Red cell count 
S/P-Calcium, total 
B-Hematocrit (PCV)  
S/P-Creatinine 
Coagulation (1.8 mL sample) 
S/P-Glucose 
PT/INR 
S/P-Magnesium 
aPTT/TT  
S/P-Phosphate 
Urine analysis (dipstick): 
S/P-Potassium 
U-Hb/Erythrocytes/Blood 
U-Protein/Albumin 
U-Glucose 
 
U-Leucocytes 
U-Nitrites  
 
S/P-Sodium 
Serology screen (1.8 mL sample) 
HBC, HCV, HIV 
 
Pregnancy test  
Blood or urine 
aPTT: Activated partial thromboplastin time; ALT: Alanine aminotransferase; AST: Alkaline phosphatase; B: 
Blood; Hb: Haemoglobin; HBC: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency 
virus; INR: International normalised time; P: Plasma; PCV: Packed cell volume; PT: Prothrombin time; 
S: Serum; TT: Thrombin time; U: Urine. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
42 
 
Please Note.  In case a patient shows an AST or ALT ≥3×ULN or total bilirubin ≥2×ULN 
please see Appendix D ‘Actions required in cases of combined increase of aminotransferase 
and total bilirubin – Hy’s Law (HL), for further instructions. 
5.2.2 
Physical examination 
A complete physical examination will be performed during Visit 1 as indicated in the Study 
Plan (Table 1) and include an assessment of the following: general appearance, skin, head and 
neck (including ears, eyes, nose and throat), respiratory, cardiovascular, abdomen, lymph 
nodes, thyroid, musculoskeletal (including spine and extremities) and neurological systems. 
The anaesthesiologist will perform the Allen´s test to make sure there is normal flow in the 
wrist between radial and ulnar arteries. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
5.2.3 
ECG 
Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 
10 minutes.  All ECGs should be recorded with the patient in the same physical position.  For 
each time point 3 ECG recordings should be taken at about 5 minute intervals.  A standardised 
ECG machine should be used and the patient should be examined using the same machine 
throughout the study if possible. 
After paper ECGs have been recorded, the Investigator or designated physician will review 
each of the ECGs and may refer to a local cardiologist if appropriate.  A paper copy should be 
filed in the patient’s medical records.  If an abnormal ECG finding at screening or baseline is 
considered to be clinically significant by the Investigator, it should be reported as a concurrent 
condition.  For all ECGs details of rhythm, ECG intervals and an overall evaluation will be 
recorded. 
ECG data will be collected digitally and will be transferred electronically for central analysis as 
described in the study specific ECG manual.  The investigator may choose to perform a non-
digital ECG at the time of the screening visit in order to identify patients eligible for study entry. 
If a non-digital ECG is performed at the screening visit it cannot subsequently be used as a 
baseline recording, in this situation an ECG will need to be collected on the baseline visit in 
digital form. 
Heart rate, PR, R-R, QRS and QT intervals will be determined and reviewed by an external 
cardiologist. 
If there is a clinically significant abnormal ECG finding during the treatment period, this should 
be recorded on the AE pCRF, according to standard AE collection and reporting processes (see 
Section 6.3.6).  A 28-day follow-up assessment will be required if an on-treatment assessment 
was abnormal at the time of discontinuation of the IP or study, to confirm reversibility of the 
abnormality.  Information on osimertinib dose reduction for QTc interval prologation is detailed 
in Section 6.8.4. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
43 
 
5.2.4 
Echocardiogram/ MUGA scan 
An ECHO or MUGA scan to assess LVEF will be performed at screening (prior to first dose 
of TAGRISSO) and at least every 16 weeks throughout the treatment period.  The modality of 
the cardiac function assessments must be consistent within a patient ie, if echocardiogram is 
used for the screening assessment then ECHO should also be used for subsequent scans.  The 
patients should also be examined using the same machine and operator whenever possible, 
and quantitative measurements should be taken.  A 28-day follow-up assessment will be 
required if an on treatment assessment was abnormal at the time of discontinuation of study 
therapy, to confirm reversibility of the abnormality  
5.2.5 
Vital signs 
Vital signs will be measured at the times specified in the Study Plan (Table 1) and recorded in 
the pCRF.  However, the Investigator reserves the right to add extra assessments if there are 
any abnormal findings for any reason the Investigator feels meets this requirement. 
5.2.5.1 
Pulse and blood pressure 
Supine BP and pulse/heart rate will be measured using a semi-automatic BP recording device 
with an appropriate cuff size after the patient has rested for approximately 10 minutes.   
As as guide, any readings outside the following should be considered in the evaluation: 
 
• 
Systolic BP >140 mmHg 
• 
Diastolic BP >90 mmHg 
• 
Heart rate <35 bpm or >100 bpm 
5.2.5.2 
Body temperature 
Body temperature will be measured using a semi-automatic body temperature recording 
device in accordance with local practice. 
5.2.5.3 
Height and weight 
Height (cm) and weight (kg) will be evaluated at screening and BMI (kg/m2) will be 
calculated.  Patients will be required to remove their shoes and wear light indoor clothing for 
these measurements.  
5.3 
Other assessments 
5.3.1 
Ophthalmologic exam 
Full ophthalmic assessment, including slit lamp examination, should be performed at 
screening and if a patient experiences any visual symptoms (including blurring of vision), 
with additional tests if clinically indicated.  Ophthalmology examination results should be 
collected in the pCRF. 
Any clinically significant findings, including those confirmed by the ophthalmologist must be 
reported as an AE.  Photographs should be performed to record any clinically significant 


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PPD


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
48 
 
AstraZeneca ensures the organisations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study centre. 
5.8 
Volume of blood 
The number of blood samples that will be drawn from each patient is shown in Table 3.  
Additional details will be described in a separate Laboratory Manual. 
Table 3 
Volume of blood to be drawn from each patient 
Assessment 
Sample volume 
(mL) 
No of samples 
Total volume 
(mL) 
Blood chemistry 
2.7 
5 
13.5 
Coagulation 
1.8 
3 
5.2 
Haematology 
2.7 
5 
13.5 
Serology 
1.8 
1 
1.8 
Osimertinib PK 
2 
10 (5×2) 
20 
Biomarkers 
20 
5 
100 
EGFR mutation 
20 
2 
40 
Arterial blood radioactivity measurements  
25 
2 (or 3) 
75 (or 100) 
Arterial blood radioactivity and metabolite 
measurements (manual blood samples) 
2 
20 (or 30) 
40 (or 60) 
Arterial blood radioactivity and metabolite 
measurements (manual blood samples) 
4 
8 (or 12) 
32 (or 48) 
Venous blood radioactivity and metabolite 
measurements 
4 
18 (or 24) 
72 (or 108) 
Total 
86 
79 (100) 
413 (or 510) 
ABSS: Automatic blood sampling system; PET: Positron emission tomography; PK: Pharmacokinetics. 
Note: arterial blood sampling includes ABSS used for the first 5 minutes, 5 mL/min.  Manual blood samples will 
be in the range of 2 to 4 mL, not exceeding 40 mL.  The study will include 2 PET examinations with arterial 
blood sampling and the third PET examination may omit arterial blood sampling.  
Additional 50 mL blood may be drawn if repeated laboratory tests are needed or if PET examination protocol 
needs adjustment.  The maximum volume to be drawn from each patient will not exceed 550 mL. 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
49 
 
6.1 
Definition of adverse events 
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no IP has been administered. 
6.2 
Definitions of serious adverse event 
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils 1 or more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation.  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect. 
• 
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent 1 of the outcomes listed above. 
For further guidance on the definition of a SAE, see Error! Reference source not found. to t
he CSP. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
Adverse Events will be collected throughout the study, from informed consent until the end of 
the follow up period.  Serious AEs will be collected from the time of signature of informed 
consent throughout the treatment period and including the follow up period.  The follow-up 
period is defined as 30 working days after the IP is discontinued.  SAEs occurring in the 
follow-up period should be reported to AstraZeneca in the usual manner (see Section 6.4). 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the pCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s) at the end of the study, if judged necessary. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
50 
 
If an Investigator learns of any SAEs, including death, at any time after a patient has 
completed the study and he/she considers there is a reasonable possibility that the event is 
related to osimertinib, the Investigator should notify AstraZeneca. 
If patients who are gaining clinical benefit are allowed to continue the IP following data 
cut-off and/or post study completion then, as a minimum, all SAEs must continue to be 
collected and reported to Astra Zeneca Patient Safety or its representative within the usual 
timeframe. 
6.3.3 
Variables  
The following variables will be collect for each AE; 
• 
AE diagnosis/description  
• 
The date and time when the AE started and stopped 
• 
Intensity grading according to revised National Cancer Insititute CTCAE 
version 4.03 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no)  
• 
Action taken with regard to IP 
• 
AE causedd patients’ withdrawal from study (yes or no) 
• 
Outcome 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
51 
 
The grading scales found in the revised National Cancer Institute CTCAE version 4.03 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used.  A copy of the CTCAE version 4.03 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
6.3.4 
Causality collection 
The Investigator will assess causal relationship between the IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IP?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the CSP. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study centre staff: “Have you/the child had any health problems since 
the previous visit/you were last asked?” or revealed by observation will be collected and 
recorded in the pCRF.  When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately. 
6.3.6 
Adverse events based on examinations and tests 
The results from protocol laboratory tests, vital signs, ECGs and other safety assessments will 
be summarised.  Deterioration as compared to baseline in protocol-mandated parameters 
should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason 
for discontinuation of treatment with the IP, unless clearly due to progression of disease under 
study. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in nonmandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
52 
 
6.3.7 
Hy’s Law 
Cases where a patient shows an AST or ALT ≥3×ULN and total bilirubin ≥2×ULN may need 
to be reported as SAEs.  Prompt reporting of cases meeting HL criteria (via the SAE expedited 
reporting system) is required for compliance with regulatory guidelines.  The Investigator is 
responsible for, without delay, determining whether a patient meets potential Hy’s Law (PHL) 
criteria. 
Details of identification of PHL cases and actions to take are detailed in Appendix D. 
6.3.8 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease.  Expected progression of 
the patient’s cancer and/or expected progression of signs and symptoms of the cancer, unless 
more severe in intensity or more frequent than expected for the patient’s condition should be 
considered as disease progression and not as an AE. 
Events that are unequivocally due to disease progression should not be reported as an AE 
during the study. 
6.3.9 
New cancers 
The development of a new cancer should be regarded as an AE and will generally meet at 
least 1 of the serious criteria.  New cancers are those that are not the primary reason for the 
administration of the IP and have been identified after the patient’s inclusion in this study. 
They do not include metastases of the original cancer. 
6.3.10 
Handling of deaths 
All deaths that occur during the study, or within the follow-up period after the administration 
of the last administration of IP, should be reported as follows: 
• 
Death, which is unequivocally due to disease progression, should be communicated 
to the study monitor at the next monitoring visit and should be documented in the 
pCRF module, but should not be reported as a SAE during the study 
• 
Where death is not clearly due to disease progression of the disease under study the 
AE causing the death should be reported to the study monitor as an SAE within 
24 hours.  The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign a single primary cause of 
death together with any contributory causes 
• 
Deaths with an unknown cause should always be reported as a SAE but every effort 
should be made to establish a cause of death.  A post-mortem may be helpful in the 
assessment of the cause of death, and if performed a copy of the post-mortem 
results (with translation of important parts into English) should be reported in an 
expedited fashion to an AstraZeneca representative within the usual timeframe 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
53 
 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the pCRF. 
If any SAE occurs in the course of the study, then Investigators or other centre staff inform the 
appropriate AstraZeneca representatives within1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other centre staff inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day ie, immediately but no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other centre staff indicate an AE is serious in the web based data 
capture system, an automated email alert is sent to the designated AstraZeneca representative. 
If the web based data capture system is not available, then the Investigator or other study 
centre staff reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study centre staff how to proceed.  
6.5 
Overdose 
A maximum tolerated dose has not been established for Osimertinib, therefore an overdose is 
any dose which exceeds the daily dose that is defined in the clinical study protocol. 
Investigators should be advised that any patient who receives a higher dose than that intended 
should be monitored closely, managed with appropriate supportive care and followed up 
expectantly. 
Such overdoses should be recorded as follows: 
• 
An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms 
on the relevant AE/SAE modules in the pCRF and on the overdose pCRF module. 
• 
An overdose with no associated symptoms is only reported on the overdose pCRF 
module. 
If an overdose occurs in the course of the study, then Investigators or other centre staff inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
54 
 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.  
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca during the 
course of the study and within 6 weeks of the last administration of osimertinib. 
6.6.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, osimertinib should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (normal birth, spontaneous miscarriage, elective termination, ectopic 
pregnancy, or congenital abnormality) should be followed up and documented even if the 
patients was discontinued from the study. 
If any pregnancy occurs in the course of the study or within 6 weeks of the final 
administration of the IP, then the Investigator or other centre staff informs the appropriate 
AstraZeneca representatives within 1 day ie, immediately but no later than 24 hours of when 
he or she becomes aware of it and enters this into the pregnancy report pCRF. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the pCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy. 
6.6.2 
Paternal exposure  
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (normal birth, spontaneous miscarriage, elective termination, 
ectopic pregnancy, or congenital abnormality) should, if possible, be followed up and 
documented.   
To capture information about a pregnancy from the partner of a male patient, the male 
patient’s partner consent must be obtained to collect information related to the pregnancy and 
outcome; the male patient should not be asked to provide this information.  A consent form 
specific to this situation must be used.  The outcome of any conception occurring from the 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
55 
 
date of the first administration until 4 months after the last administration should be followed 
up and documented.   
However, the Investigator should report pregnancies according to the procedures and 
timelines described for reporting of SAEs.  The pregnancy report form should be used instead 
of the SAE form. 
6.7 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca IP that either causes harm to the patient or has the 
potential to cause harm to the patient  
A medication error is not lack of efficacy of the IP, but rather a human or process related 
failure while the IP is in control of the study centre staff or patient. 
Medication error includes situations where an error:  
• 
Occurred 
• 
Was identified and intercepted before the patient received the IP 
• 
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
• 
Investigational product name confusion. 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually 
given to the patient. 
• 
Investigation product not administered as indicated, for example, wrong route or 
wrong site of administration. 
• 
Investigational product not taken as indicated eg, tablet dissolved in water when it 
should be taken as a solid tablet . 
• 
Investigational product not stored as instructed eg, kept in the fridge when it should 
be at room temperature. 
• 
Wrong patient received the medication.  
• 
Wrong IP administered to patient.  
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting to those which lead to 1 of the above listed events that 
would otherwise have been a medication error.  
• 
Patient accidentally missed IP administration(s) eg, forgot to take medication. 
• 
Accidental overdose (will be captured as an overdose). 
• 
Patient failed to return unused medication or empty packaging. 
• 
Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product.  


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
56 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
If an medication error occurs in the course of the study, then the Investigator or other centre 
staff informs the appropriate AstraZeneca representatives within 1 day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors. 
6.8 
Management of IP related toxicities  
Patients who have IP-related toxicities requiring dose interruption or dose reduction may be 
discontinued from the imaging phase and entered into the CAP following discussion with an 
AstraZeneca representative.  Dose reduction is not allowed in the imaging phase of the study; 
if the Investigator feels that they need to reduce the IP dose due to toxicity, then the patient 
should be discontinued from the imaging phase and may be entered into the CAP. 
The following text is guidance for Investigators who treat patients with osimertinib in 
continued access: 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), 
including a dose-limiting toxicity not attributable to the disease or disease-related processes 
under investigation, dosing will be interrupted and supportive therapy administered as 
required in accordance with local practice/guidelines. 
If dose reduction is necessary, then the dose of osimertinib should be reduced to 40 mg taken 
once daily.  Patients who reduce to the 40 mg dose must remain on the 40 mg dose for the 
remainder of the study. 
Dose interruption and reduction guidelines are provided in Table 4. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
57 
 
Table 4 
Osimertinib dose adjustment information for adverse reactions 
Target Organ 
Adverse Reaction 
Dose Modification  
Pulmonary  
ILD/Pneumonitis 
Permanently discontinue 
osimertinib  
Cardiac 
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 481 msec within 
3 weeks of onset, then restart 
at a reduced dose (40 mg) or 
at 80mg (at the discretion of 
the investigator). 
QTc interval prolongation with 
signs/symptoms of serious arrhythmia 
Permanently discontinue 
osimertinib 
 
Other  
Grade 3 or higher adverse reaction 
Withhold osimertinib for up to 
3 weeks  
If grade 3 or higher adverse reaction improves 
to grade 0-2 after withholding of osimertinib 
for up to 3 weeks  
Osimertinib may be restarted 
at the same dose (80 mg) or a 
lower dose (40 mg) 
Grade 3 or higher adverse reaction that does 
not improve to grade 0-2 after withholding for 
up to 3 weeks  
Permanently discontinue 
osimertinib  
ECG: Electrocardiogram; ILD: Interstitial lung disease; msec: Millisecond; QTc:QT interval corrected. 
If a toxicity resolves or reverts to ≤CTCAE grade 2 within 3 weeks of onset, treatment with 
osimertinib may be restarted at the same dose (80 mg) or a lower dose (40 mg) using the rules 
below for dose modifications (Table 5) and with discussion and agreement with the 
AstraZeneca study team physician as needed.  There will be no individual modifications to 
dosing schedule in response to toxicity, only potential dose reduction or dose interruption. 
If the toxicity does not resolve to ≤CTCAE grade 2 after 3 weeks, then the patient should be 
withdrawn from the study and observed until resolution of the toxicity. 
Table 5 
Dose interventions 
Intervention 
Osimertinib Dose 
Starting dose procedure for discontinuation 
80 mg 
Reduced Dose –1 
40 mg 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
58 
 
On resolution of toxicity within 3 weeks: 
If an AE subsequently requires dose interruption, osimertinib may be restarted at the same 
dose or at the reduced dose, on resolution/improvement of the AE at the discretion of the 
Investigator. 
6.8.1 
Skin reactions 
Recommendations for appropriate management of skin reactions, including guidance on dose 
adjustments for clinically significant and/or intolerable skin reactions that are considered by 
the Investigator to be causally related to osimertinib is provided in osimertinib IB. 
The following is not applicable to the patients in continued access: 
Skin reactions are to be reported as AEs in the pCRF, with additional details captured in the 
"SKNREAC" pCRF: 
• 
Changes in the characteristics of skin reactions will be collected in the 
"SKNREAC" pCRF 
• 
Changes in the CTCAE grade of skin reactions will be collected in the AE pCRF 
Photographs of skin reactions may be collected and these photographs should be available for 
central review by AstraZeneca and for external expert dermatological review if required.  Skin 
biopsies may be taken of skin reactions. 
6.8.2 
Diarrhoea 
Recommendations for appropriate management of diarrhoea, including dose-adjustments for 
AEs of diarrhoea that are of CTCAE grade ≥3 or that are clinically significant and/or 
intolerable and considered by the Investigator to be causally related to osimertinib are 
available in IB.  During the imaging phase, changes in CTCAE grade of diarrhoea will be 
captured in the AE pCRF. 
6.8.3 
ILD/Pneumonitis-like toxicity 
If new or worsening pulmonary symptoms (eg, dyspnoea) or a radiological abnormality 
suggestive of ILD/pneumonitis is observed, an interruption in IP administration is 
recommended. The results of the full diagnostic workup (including high-resolution computed 
tomography [HRCT], blood and sputum culture, haematological parameters) will be captured 
in the pCRF during the imaging phase.  During the CAP, a questionnaire regarding the results 
of the full diagnostic workup may be sent to the Investigators.  All image data should also be 
provided to AstraZeneca.  It is strongly recommended to perform a full diagnostic workup, to 
exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic 
edema, or pulmonary haemorrhage.  In the presence of confirmatory HRCT scans where other 
causes of respiratory symptoms have been excluded, a diagnosis of ILD/pneumonitis should 
be considered and the IP permanently discontinued (per Table 4 above). 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
59 
 
Patients experiencing ILD/pneumonitis will not be permitted to restart the IP.  In the absence 
of a diagnosis of ILD/pneumonitis, the IP may be restarted. 
An AstraZeneca or representative study team physician must be contacted. 
6.8.4 
QTc prolongation 
In light of the potential for QT changes associated with osimertinib, electrolyte abnormalities 
(hypokalemia, hypomagnesemia, hypocalcemia) must be corrected to be within normal ranges 
prior to first dose and electrolyte levels monitored during study treatment 
Refer to Table 4 above.  Patients with QTcF prolongation to >500 msec should have study 
treatment interrupted and regular ECGs performed until resolution to <481 msec, or recovery 
to baseline if baseline QTcF is ≥ 481 msec and then restarted at a reduced dose of 40mg, or 
80mg at the discretion of the investigator. If the toxicity does not resolve to ≤ grade 1 within 
21 days the patient will be permanently withdrawn from study treatment. The Investigator or 
designated physician should review each ECG prior to discharge and may refer to a local 
cardiologist if appropriate for immediate management of the patient. 
 
6.8.5 
Keratitis and corneal ulceration 
Keratitis was reported in 0.7% (n=6) of the 833 patients treated with osimertinib in the AURA 
studies.  Patients presenting with signs and symptoms suggestive of keratitis such as acute or 
worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red 
eye should be referred promptly to an ophthalmology specialist.  Any patient developing 
corneal ulceration will be permanently discontinued from the IP (see Table 4) and should be 
followed regularly until resolution of the event.  Corneal ulceration should be treated 
according to local guidance. 
6.8.6 
Changes in cardiac contractility  
Across clinical studies, LVEF decreases greater than or equal to 10% and a drop to less than 
50% occurred in 4.0% (26/655) of patients treated with osimertinib who had baseline and at 
least 1 follow-up LVEF assessment.  Based on the available clinical study data, a causal 
relationship between effects on changes in cardiac contractility and osimertinib has not been 
established.  In patients with cardiac risk factors and those with conditions that can affect 
LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, 
should be considered. In patients who develop relevant cardiac signs/symptoms during 
treatment, cardiac monitoring including LVEF assessment should be considered.  


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
61 
 
Investigational product manufacturing, labelling, packaging and release will be conducted following Good 
Manufacturing Practice (GMP). 
7.2 
Dose and treatment regimens 
Radioligand [11C]osimertinib will be administered IV, synchronized with the start of the PET 
system examination.  Each patient will undergo a single administration of [11C]osimertinib 
repeated 3 times over the study (Day 1, Day 2 [or up to Day 8] and Day 29).  Mass injected 
will not exceed 10 μg per injection.  Radioactivity injected will be 300 MBq/70 kg of body 
weight.  The minimum injected radioactivity will be 200 MBq/70 kg body weight and the 
maximum radioactivity injected will be 330 MBq/70 kg body weight. 
The first administration of [11C]osimertinib will be administered on Day 1 in the clinic via an 
IV route.  After 90 minutes of the PET examination, the patient may be discharged from the 
clinic. 
The second administration of [11C]osimertinib will be approximately 6 hours after the single 
oral 80 mg administration of osimertinib to coincide with the oral Tmax.  The oral 
administration can be with or without food.  Pharmacokinetic samples will be collected (up to 
6 hours) and the PET examination will be conducted for 90 minutes (minimum 60 minutes) 
after the IV administration is given.  This visit can happen on Day 2 (1 day after the first IV 
administration) and up to Day 8.  
Osimertinib 80 mg once a day will be taken by the patient from the day of the second PET 
examination for at least 21 days before the PET3 examination will be scheduled.  On Day 14 
(±2 days), a clinical visit to evaluate the safety of the patient will be performed.  
Patients will come to the clinic on Day 29 (±3 days), prior to taking their daily dose of 
osimertinib.  It is important to record date/time of the last administration taken before the visit 
and make sure that the trough (pre-administration) sample is collected no less than 18 hours 
and no more than 30 hours after the last administration before the PK blood sample.  On Day 
29, in addition to receiving their daily administration of osimertinib, patients will receive 
[11C]osimertinib via IV route at approximately 6 hours after the oral administration.  Safety 
information will be collected during this visit and the patient will be discharged after the PET 
examination is finished.  Computed tomography/MRI measurement can be conducted on the 
same day or within 7 days of this visit. 
7.3 
Labelling 
Labels will be prepared in accordance with GMP and local regulatory guidelines.  The labels 
will fulfil GMP Annex 13 requirements for labelling.  Label text will be translated into local 
language. 
The label will include the following information: 
For the [11C]osimertinib the vial with the prepared radiolabelled osimertinib will be labelled 
with the following information: signature of the responsible radiochemist, name of the PET 
ligand: “[11C]osimertinib”, batch number, date and time of injection.  In addition the vial will 


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PPD


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
63 
 
• 
Deliveries of such products from AstraZeneca or its representative are correctly 
received by a responsible person. 
• 
Such deliveries are recorded. 
• 
Investigational products are handled and stored safely and properly as stated on the 
label. 
• 
Investigational products are only dispensed to study patients in accordance with the 
CSP. 
The study staff will account for all IP dispensed and returned. 
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock.  Records of usage should include the identification of the person 
to whom the IP was dispensed, the quantity and date of dispensing, and unused IP returned to 
the Investigator.  This record is in addition to any IP accountability information recorded on 
the pCRF.  Any discrepancies must be accounted for on the appropriate forms.  Certificates of 
delivery and return must be signed, preferably by the Investigator or a pharmacist, and copies 
retained in the Investigator centre file.  Dispensing and accountability records will continue to 
be collected after the end of the imaging phase for as long as patients continue to receive IP. 
7.7 
Concomitant and other treatments  
Information on any treatment in the 2 weeks prior to starting the IP and all concomitant 
treatments given during the study, with reasons for the treatment, will be recorded in the 
pCRF.  
Please see Appendix B for medication that may potentially have interactions with osimertinib. 
7.7.1 
Other concomitant treatment 
Medication other than that described in Appendix B, which are considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the pCRF. 
7.8 
Post study access to study treatment 
On completion of the imaging phase (ie, at the PET3 examination), patients may continue to 
take osimertinib tablets (80 mg once daily) as a single agent in continued access if they and 
the Investigator agree that this is appropriate.  This will continue until the Investigator 
believes they are no longer deriving clinical benefit, or they stop taking osimertinib for any 
other reason.  No clinical data will be collected during this phase other than sudden death of 
unknown reason, SAEs that may or may not be related to osimertinib, outcomes of pregnancy 
and IP dispensing/accountability.  


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
65 
 
8.4 
Outcome measures for analyses 
The primary outcome variables describe the distribution of [11C]osimertinib in the brain using 
a set of exposure parameters including but not limited to: 
• 
The maximum concentration in the whole brain, expressed as the %ID:  
Cmax, %ID brain or as SUV Cmax, SUV brain  
• 
The time to the maximum radioactivity concentration in brain: Tmax brain  
• 
Brain plasma partition coefficient (ratio of radiolabelled osimertinib concentration 
in brain to that in plasma) as AUCbrain 0-90min/AUCblood 0-90min.  The area under the 
brain as well as the plasma radioactivity concentration-time curve between 0 and 90 
minutes after injection (AUC0-90 min) will be calculated by the linear trapezoidal rule. 
8.5 
Methods for statistical analyses 
The analysis will be descriptive and consist of patient listings, graphs, summary statistics 
comprising geometric mean, arithmetic mean, standard deviation (SD), median, minimum and 
maximum values as appropriate. 
8.5.1 
Patient disposition 
Continuous variables will be summarised using descriptive statistics (n, mean, SD, minimum, 
median and maximum) by phase.  Categorical data will be summarised using frequencies and 
percentages by phase where applicable. 
8.5.2 
Demographic and baseline data 
Demographic and baseline characteristic data recorded at the screening Visit will be listed.  
Demographic data will include date of birth, age, sex, race and ethinicity.  Patient 
characteristics and baseline data will include smoking details (quatity and duration of smoking 
history) and physical examination findings.   
8.5.3 
Exposure 
Exposure to IP i.e., total amount of IP received will be described for all patients. 
8.5.4 
PET imaging and RECIST 
Parameters from PET imaging (Section 8.5.7) will be summarised.  Overall response from the 
BM assessment according to CNS RECIST v1.1 from the brain MRI after 3 weeks of multiple 
administrations will be summarised.  Modified RECIST criteria, referred to here as CNS 
RECIST, will allow the selection of up to 5 lesions in the brain as target lesions, in contrast to 
RECIST 1.1 which categorises brain metastases as non-measurable lesions. Overall response 
from the extra-cranial tumour assessment according to RECIST v1.1 from thorax/abdomen 
CT after 3 weeks of multiple administrations will also be summarised. 
8.5.5 
Pharmacokinetics 
Pharmacokinetic parameters include Cssmax, tssmax, AUCss for osimertinib (parent), and the 
metabolite to parent ratio of AUCss and Cssmax for AZ5104, as appropriate. 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
67 
 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study centre staff 
Before the first patient is entered into the study, an AstraZeneca representative will visit the 
study centre to review and discuss the requirements of the CSP and related documents with 
the investigational staff and also to train them in any study specific procedures including 
collection of samples.  The Investigator will ensure that appropriate training relevant to the 
study is given to all of the staff, and that any new information relevant to the performance of 
this study is forwarded to the staff involved. 
The Investigator will maintain a record of all staff members involved in the study (medical, 
nursing and other staff). 
9.2 
Monitoring of the study 
The AstraZeneca and IQVIA (formerly Quintiles IMS) representatives will be available 
between visits if the Investigator(s) or other staff at the centre that needs information and 
advice about the study conduct. 
During the study, an IQVIA (formerly QuintilesIMS) representative will have regular contacts 
with the study centres, including visits to: 
• 
Provide information and support to the Investigator(s). 
• 
Confirm that facilities remain acceptable. 
• 
Confirm that the investigational team is adhering to the CSP including the specific 
requirements, that data are being accurately and timely recorded in the pCRFs, and 
that IP accountability checks are being performed. 
• 
Perform source data verification (a comparison of the data in the pCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of the informed consent forms (ICFs) of 
participating patients.  This will require direct access to all original records for each 
patient (eg, clinic charts). 
• 
If applicable, ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the patient. 
9.2.1 
Source data 
Refer to the CSA for location of source data. 
9.2.2 
Study agreements 
The Investigator at the centre should comply with all the terms, conditions, and obligations of 
the CSA, or equivalent, for this study.  In the event of any inconsistency between this CSP and 
the CSA, the terms of CSP shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the CSA shall prevail. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
68 
 
Agreements between AstraZeneca and the Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of the study is defined as after the last patient has left the CAP. 
The study may be terminated if the study procedures are not being performed according to 
Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with osimertinib. 
9.3.1 
Study and site closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The study may be stopped if, in the 
judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that:  
· 
meet individual stopping criteria or are otherwise considered significant  
· 
are assessed as causally related to study drug,  
· 
are not considered to be consistent with continuation of the study  
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.  
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.  
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:  
· 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines  
· 
Inadequate recruitment of participants by the investigator  


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
69 
 
· 
Discontinuation of further study intervention development. 
9.4 
Data management by AstraZeneca  
Data management will be performed by the CRO on behalf of AstraZeneca, according to the 
Data Management Plan. 
When the completed paper CRFs have been scanned and indexed, the data are entered into the 
study database and proofread. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
9.4.1 
SAE reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the study centre.  
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
10.2 
Patient data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
70 
 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the patients. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient.  For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also Regulatory Authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final CSP, including the final version of the 
ICF and any other written information and/or materials to be provided to the patients.  The PI 
will ensure the distribution of these documents to the applicable EC, and to the study centre 
staff. 
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca before enrolment of any patient into the study.  The EC should 
approve all advertising used to recruit patients for the study.  AstraZeneca should approve any 
modifications to the ICF that are needed to meet local requirements.  If required by local 
regulations, the protocol should be re-approved by the EC annually. 
The PI is responsible for providing the EC/Institutional Review Board with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP. 
AstraZeneca will provide this information to the PI so that he/she can meet these reporting 
requirements. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, EC and the PI with safety updates/reports 
according to local requirements, including Suspected Unexpected Serious Adverse Reactions, 
where relevant. 
10.4 
Informed consent 
The PI at the centre will: 
• 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study. 
• 
Ensure each patient is notified that they are free to discontinue from the study at any 
time. 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
71 
 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
• 
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• 
Ensure a copy of the signed ICF is given to the patient 
• 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC. 
Any incentives for patients who participate in the study as well as any provisions for patients 
harmed as a consequence of study participation should be described in the informed consent 
form that is approved by an Ethics Committee. 
The PI at the PET centre will: 
• 
Ensure that each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study Ensure that each 
patient is notified that they are free to withdraw from the study or the research 
components at any time 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
• 
Ensure each original, signed ICF is stored in the Investigator’s Study File  
• 
Ensure a copy of each signed ICF is given to the patient. 
10.5 
Changes to the Clinical Study Protocol and Informed Consent 
Form 
If there are any substantial changes to the CSP, then these changes will be documented in a 
new version of the CSP. 
The new version of the CSP is to be approved by the relevant EC and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for new versions of CSPs. 
AstraZeneca will distribute any new versions of the CSP to the PI.  For distribution to the EC 
see Section 10.3. 
If a change to a CSP requires a change to a centre’s ICF, AstraZeneca and the centre’s EC are 
to approve the revised ICF before the revised form is used.  
Study procedures will not be changed without the mutual agreement of the Investigator, and 
AstraZeneca. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC. 


Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
72 
 
If local regulations require, any administrative change will be communicated to or approved 
by the EC. 
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the CSP, GCP, guidelines of the ICH, and any 
applicable regulatory requirements.  The PI will contact AstraZeneca immediately if contacted 
by a regulatory agency about an inspection at the centre. 
 
 


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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
74 
 
Heon et al 2010 
Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al.  Development of 
central nervous system metastases in patients with advanced non-small cell lung cancer and 
somatic EGFR mutations treated with gefitinib or erlotinib.  Clin Cancer Res. 
2010;16:5873-5882. 
Koba et al 2017 
Koba T, Kijima T, Takimoto T, Hirata H, Naito Y, Hamaguchi M, et al.  Rapid intracranial 
response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring 
the EGFR T790M mutation.  Medicine (Balitmore) 2017;Feb 96(60): e6087 
Lapin and Gardner 2003 
Lappin G, Garner RC.  Big physics, small doses: the use of AMS and PET in human 
microdosing of development drugs.  Nat Rev Drug Discov. 2003;2:233-240. 
Lee and Farde 2006 
Lee CM and Farde L.  Using positron emission tomography to facilitate CNS drug 
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Lynch et al 2004 
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al.  
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non-small-cell lung cancer to gefitinib.  N Engl J Med. 2004;350:2129-2139. 
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Mujoomdar et al 2007 
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Published May 28, 2009.  V4.03, 14 June 2010.  Available from URL: http://ctep.cancer.gov. 
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National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site. 2017.  
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Pisters and Le Chevalier 2005 
Pisters KMW, Le Chevalier T.  Adjuvant chemotherapy in completely resected non-small-cell 
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Clinical Study Protocol 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
75 
 
Porta et al 2011 
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Saleem et al 2015 
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SP-PET-0052 
Positron emission tomography (PET) measurement of whole-body biodistribution of 
[11C]AZD9291 in Rhesus monkey for dosimetry calculations. 
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208065s006lbl.pdf. 
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TAGRISSO (osimertinib) PSSR, Version 20, 25 June 2019 
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Food and Drug Administration Center for Drug Evaluation and Research (CDER).  


Clinical Study Protocol Appendix A 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
76 
 
Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg., hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment. 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine. 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• 
Blood dyscrasias (eg., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation. 
Development of drug dependency or drug abuse. 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug? 


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• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


Clinical Study Protocol Appendix B 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
78 
 
Appendix A 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between risk groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
• 
Are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging.  
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content. 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


Clinical Study Protocol Appendix C 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
79 
 
Appendix B 
Guidance Regarding Potential Interactions with 
Concomitant Medications 
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 paper case report form (pCRF). 
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 C1 
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. 


Clinical Study Protocol Appendix C 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
80 
 
2. Medicines Whose Exposures may be Affected by Osimertinib that AstraZeneca 
Considers may be Allowed with Caution 
Osimertinib may increase the concentration of sensitive BCRP and Pgp substrates  
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive Pgp substrate,  
fexofenadine, are increased). 
Table C2 
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 coadministration 
with osimertinib. 
Sulfasalazine 
Doxorubicin 
Daunorubicin 
Topotecan 
Dabigatran 
 
Aliskiren 
 
Digoxin 
 
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 on the CredibleMeds® website 
https://www.crediblemeds.org/. The website categorizes drugs based on the risk of inducing 
Torsade de Pointes (TdP).   
During screening the drugs that patients are currently receiving (prescription and 
nonprescription) should be checked opposite the ArizonaCert website. In addition, drugs 
intended for use following study treatment initiation should be checked opposite the website.  
3.1 Drugs with a known risk of Torsades de Pointes 
 Drugs in this category are known to prolong the QT interval and are clearly associated with a 
known risk of TdP, even when taken as recommended  
3.1.1 Before commencing study treatment  
Drugs in the category of known risk of TdP must have been discontinued prior to the start of 
administration of study treatment in accordance with guidance provided in Table C3.  
 


Clinical Study Protocol Appendix C 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
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3.1.2 During study treatment  
It is recommended that drugs in the category of known risk of TdP are not co-administered 
with study treatment (osimertinib) and for a period of two weeks after discontinuing study 
treatment, however if it is considered essential for patient management to co-administer these 
drugs with study treatment (osimertinib) close monitoring with ECGs and electrolytes is 
recommended.  
The list of drugs may not be exhaustive and is subject to change as new information becomes 
available. As such investigators are recommended to search the CredibleMeds® website 
(https://www.crediblemeds.org/) to provide the most up to date information.  
 
Table C3 
Drugs with a known risk of TdPa 
Contraindicated drug 
Withdrawal period prior to 
osimertinib start 
Aclarubicin, Anagrelide, Ciprofloxacin, Clarithromycin, 
Cocaine, Droperidol, Erythromycin, Levofloxacin, 
Ondansetron, Papaverine hydrochloride, Procainamide, 
Sulpiride, Sultopride, Terfenadine Terlipressin 
2 days 
Cilostazol, Cisapride, Disopyramide, Dofetilide, Domperidone, 
Flecainide, Gatifloxacin, Grepafloxacin, Ibutilide, 
Moxifloxacin, Oxaliplatin, Propofol, Quinidine, 
Roxithromycin, Sevoflurane, Sotalol, Sparfloxacin, 
Thioridazine 
7 days 
Azithromycin, Bepridil, Citalopram, Chlorpromazine, 
Dronedarone, escitalopram, Fluconazole, Halofantrine, 
Haloperidol, Levomepromazine, Levosulpiride, Mesoridazine 
14 days 
Donepezil, Terodiline 
3 weeks 
Levomethadyl, Methadone, Pimozide 
4 weeks 
Arsenic trioxideb, Ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, Probucol, Vandetanib 
4 months 
Amiodarone, Chloroquine 
1 year 
a This list should be checked against the full and most current list presented in the CredibleMeds® website (https://www.crediblemeds.org/)  
b Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
 
 
 


Clinical Study Protocol Appendix C 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
82 
 
3.2 Other TdP risk Categories   
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from other 
TdP risk categories can be enrolled, notwithstanding other exclusions and restrictions, if these 
drugs are considered essential for patient management and the patient has been stable on 
therapy. Close monitoring with ECGs and electrolytes is recommended.  
Patients with congenital long QT syndrome (CLQTS) are excluded from this study.  
3.3 Guidance regardless of TdP risk category  
During study treatment and for a period of two weeks after discontinuing study treatment if it 
is considered essential for patient management to co-administer drugs known to prolong QTc 
interval, regardless of TdP risk category, close monitoring with ECGs and electrolytes is 
recommended. 


Clinical Study Protocol Appendix D 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
83 
 
Appendix C 
Definition of Women of Childbearing Potential and 
Acceptable Contraceptive Methods. 
Definition of Women of Childbearing Potential 
Women of Childbearing Potential (WoCBP): 
Women between menarche and menopause who have not been permanently or surgically 
sterilised and are capable of procreation. 
Women NOT of Childbearing Potential: 
Women who are permanently or surgically sterilised or post-menopausal (definitions below): 
Permanent sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion.  Tubal occlusion is considered a highly 
effective method of birth control but does not absolutely exclude possibility of pregnancy. 
(The term occlusion refers to both occluding and ligating techniques that do not physically 
remove the oviducts). 
• 
Women who have undergone tubal occlusion should be managed on trials as if they 
are of WoCBP (eg, undergo pregnancy testing etc, as required by the CSP). 
• 
Women will be considered post-menopausal if they are amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements 
apply: 
• 
Women under 50 years old will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range. 
• 
Women over 50 years of age will be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments. 
Acceptable contraception methods 
Highly effective method of birth control is defined in Note 3 in ICH Guidance M3 
(Nonclinical Safety Studies for the conduct of Human Clinical trials for Pharmaceuticals) as 
one that results in a low failure rate (eg, less than 1 percent per year) when used consistently 
and correctly. 
Note that women should have been stable on their chosen method of birth control for a 
minimum of 2 weeks before entering the trial. Generic names and examples of trade names 
are given. As trade names may vary, investigators should check the generic name of any 
contraception to ensure suitability. 
 
 


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Acceptable contraception methods are: 
• 
Total sexual abstinence (abstinence must be for the total duration of the trial and the 
follow-up period). 
• 
Vasectomised sexual partner plus male condom (with participant assurance that 
partner received post-vasectomy confirmation of azoospermia). 
• 
Tubal occlusion plus male condom 
• 
Intra-uterine Device (IUD) - provided coils are copper-banded, plus male 
condomIntra-uterine system (IUS) Levonorgestrel Intra Uterine System (eg, 
Mirena), plus male condom. 
• 
Medroxyprogesterone injections (Depo-Provera) plus male condom. 
• 
Etonogestrel implants (eg, Implanon, Norplan) plus male condom. 
• 
Normal and low dose combined oral contraceptive pills, plus male condom. 
• 
Norelgestromin/ethinylestradiol transdermal system plus male condom 
• 
Intravaginal device (eg, ethinylestradiol and etonogestrel) plus male condom. 
• 
Cerazette (desogestrel) plus male condom. Cerazette is currently the only highly 
efficacious progesterone based pill. 
Unacceptable contraception methods 
The following methods are considered not to be highly effective and are therefore not 
acceptable contraceptive methods in AstraZeneca clinical trials: 
• 
Triphasic combined oral contraceptives (COCs) 
• 
All progesterone only pills except, Cerazette 
• 
All barrier methods, if intended to be used alone 
• 
Non-copper containing Intra-Uterine Devices (IUDs) 
• 
Fertility awareness methods 
• 
Coitus interruptus


Clinical Study Protocol Appendix E 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
 
85 
 
Appendix D 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
1. Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.   
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 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 
Product (IP).  
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  
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3×Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2×ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  
A Potential Hy’s Law (PHL) case is defined as a study patient with an increase in serum AST 
or ALT ≥3×ULN together with total bilirubin (TBL) ≥2×ULN irrespective of serum ALP, at 
any point during the study following the start of study medication. 
Hy’s Law  
AST or ALT ≥3×ULN together with TBL ≥2×ULN, where no other reason, other than the IP, 
can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
A HL case is defined as a study patient with an increase in serum AST or ALT 
≥3×ULN together with TBL ≥2×ULN, where no other reason can be found to explain the 
combination of increases, eg, elevated serum ALP indicating cholestasis, viral hepatitis, 


Clinical Study Protocol Appendix E 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
 
86 
 
another drug.  For PHL and HL to be met the elevation in transaminases must precede or be 
coincident with (ie, 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 ≥3×ULN 
• 
AST ≥ 3×ULN 
• 
TBL ≥2×ULN 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
• 
Notify the AstraZeneca representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory 
• 
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result. 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• 
Determine whether the patient meets PHL criteria (see Section 2. Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results). 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the patient meets PHL criteria (see Section 2. Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF. 


Clinical Study Protocol Appendix E 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
 
87 
 
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 CSP. 
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 (see Section 6. Actions Required when Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment). 
• 
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 patients’ 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.  For studies using a central laboratory add: This includes 
deciding which the tests available in the HL lab kit should be used.  
• 
Complete the 3 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 IP.  
The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
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: 


Clinical Study Protocol Appendix E 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
 
88 
 
• 
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 IP: 
• 
Report an SAE (report term ‘HL’) 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 ‘PHL’) 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 amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 
6. Actions Required when Potential Hy’s Law Criteria are Met Before and After 
Starting Study Treatment  
This section is applicable to patients with liver metastases who meet PHL criteria on 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 patients’ condition# compared 
with the last visit where PHL criteria were met#  
− 
If there is no significant change no action is required 
− 
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 Potential Hy’s Law Criteria met of this Appendix. 


Clinical Study Protocol Appendix E 
Drug Substance [11C]osimertinib, osimertinib  
Study Code D5160C00043 
Version 2.0 
Date 24 September 2019 
 
89 
 
# A ‘significant’ change in the patient’s condition refers to a 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.  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 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 found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver 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. Actions 
Required when Potential Hy’s Law Criteria are Met Before and After Starting Study 
Treatment? 
If No: follow the process described in Section 4.2 Potential Hy’s Law Criteria met 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 4.2 of this 
Appendix. 
# A ‘significant’ change in the patient’s condition refers to a 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.  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. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’ 

SAP_001.pdf: 
 
Statistical Analysis Plan 
Study Code 
D5160C00043 
Edition Number 1.0 
Date 
17AUG2018 
An Open-label Positron Emission Tomography (PET) Study to Determine 
Brain Exposure of Osimertinib after Intravenous Microdose 
Administration of [11C]osimertinib and Therapeutic Oral Doses of 
Osimertinib to Patients with EGFR Mutated Non-Small Cell Lung Cancer 
and Brain Metastases 
 
 
 
 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
2 
 
 
 
 
 
 
 
 
An Open-label Positron Emission Tomography (PET) Study to Determine 
Brain Exposure of Osimertinib after Intravenous Microdose 
Administration of [11C]osimertinib and Therapeutic Oral Doses of 
Osimertinib to Patients with EGFR Mutated Non-Small Cell Lung Cancer 
and Brain Metastases 
 
 
Study Statistician IQVIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
6 
4.3 
Analysis methods ................................................................................................... 22 
4.3.1 
Screening and demographic measurements ........................................................... 22 
4.3.2 
Important protocol deviations ................................................................................ 23 
4.3.3 
Safety parameters ................................................................................................... 24 
5. 
INTERIM ANALYSES (NOT APPLICABLE) .................................................... 25 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 25 
7. 
REFERENCES ...................................................................................................... 26 
8. 
APPENDIX (NOT APPLICABLE) ....................................................................... 26 
 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
7 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
AUCss 
Area under the concentration-time curve at steady state 
BM 
Brain metastases 
BMI 
Body mass index 
BP 
Blood pressure 
CSR  
Clinical Study Report 
11C 
Carbon-eleven 
Cmax 
Maximum concentration after single dose 
Cssmax 
Maximum concentration at steady state 
CAP 
Continued access phase 
CNS 
Central nervous system 
CRF 
Case report form (paper) 
CSF 
Cerebrospinal fluid 
CSP 
Clinical Study Protocol 
ctDNA 
Circulating tumour DNA 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EGFR 
Epidermal growth factor receptor 
FSH 
Follicle-stimulating hormone 
GCV 
Geometric coefficient of variation 
IP 
Investigational Product 
Kpu,u 
Brain/plasma partition coefficient 
LM 
Leptomeningeal metastases 
LVEF 
Left ventricular ejection fraction 
MedDRA  
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition angiogram 
NSCLC 
Non-small cell lung cancer 
%ID 
Percent of radioactive drug injected 
PET 
Positron emission tomography 
PK 
Pharmacokinetics 
RECIST 
Response Evaluation Criteria in Solid Tumours 
ROI 
Region of interest 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
8 
Abbreviation or 
special term 
Explanation 
SD 
Standard deviation 
SOC 
System organ class 
SUV 
Standardised uptake value 
Tmax 
Time of maximum drug concentration after single dose 
Tssmax 
Time of maximum drug concentration at steady state 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
9 
AMENDMENT HISTORY 
Date 
Brief description of change 
 
N/A 
 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
10 
1. 
STUDY DETAILS 
1.1 
Study objective 
 
Primary objective 
The primary objective of this study and the associated outcome measures are 
Primary Objective: 
Outcome Measure: 
To determine the brain exposure of 
[11C]osimertinib in tumour region of interest 
(ROI) [brain metastases (BM), including 
leptomeningeal metastases (LM)] in patients 
with non-small cell lung cancer (NSCLC) 
after a single intravenous (IV) microdose and 
after single and multiple therapeutic doses of 
osimertinib 
The percent of injected dose in the whole brain 
(%ID) and brain standard uptake value (SUV), to 
describe maximal radioactivity concentration in the 
brain (Cmax,%ID brain; Cmax,SUVbrain). 
The time of the maximum radioactivity concentration 
in the brain (Tmax brain). 
The brain to plasma partition coefficient 
(concentration brain/plasma ratio) as area under the 
concentration-time curve                                 
(Kp=AUCbrain 0-90min/ AUCblood 0-90min). 
All parameters of exposure will include the tumour 
region, whole brain and anatomical regions. 
AUC: Area under the concentration curve; Cmax: Maximum concentration after single dose; Tmax: Time of 
maximum drug concentration after single dose. 
 
 
Secondary objective 
The secondary objective of this study and the associated outcome measures are 
Secondary Objective: 
Outcome Measure: 
To determine the pharmacokinetics (PK) of 
osimertinib and its metabolite (AZ5104) after 
multiple administrations of osimertinib 
The following variables will be calculated where the 
data allow: maximum plasma concentration (Cssmax), 
time to reach maximum plasma concentration (tssmax), 
area under the plasma concentration-time curve from 
zero to the last measurable time point (AUCss). 
Also, the metabolite to parent ratio of the AUC and 
maximum concertation after a single dose (Cmax) 
will be calculated, as appropriate. 
AUC: Area under the concentration curve; Cmax: Maximum concentration after single dose 
 
 
 
 
 


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Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
14 
1.3 
Number of subjects 
Given that this a PET study, sample size is based on the generally applied numbers in the 
exploratory pilot type studies, where 8 subjects is the accepted minimum number. These types 
of studies have no statistics to give better ground for sample size calculations. Therefore, the 
minimum sample size is accepted both by regulatory and scientific communities. Given the 
nature, no formal statistical analysis will be performed in this study. The statistical analysis 
will be descriptive. 
The number of patients is based on the desire to obtain evaluable data while exposing as few 
evaluable patients as possible to the study procedures.  Approximately 12 patients with 
NSCLC will receive osimertinib to obtain at least 8 patients to complete all study assessment 
procedures, and hence, evaluable for analysis. 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
There will be 4 analysis sets considered in this study: 
• The safety analysis set will include all patients who receive at least 1 administration of 
[11C]osimertinib and/or osimertinib  
 
• The PET analysis set will include all patients who complete at least 1 PET 
examination for the evaluation of [11C]osimertinib brain distribution.  
 
• The complete PET analysis set will include all patients who complete all three PET 
examinations. This analysis set is a subset of the PET analysis set and will be used in 
the assessment of potential treatment effects on brain metastases 
 
• The PK analysis set will include all patients who received at least 1 administration of 
either [11C]osimertinib and/or osimertinib and had post administration PK assessments 
of osimertinib and/or its metabolite (AZ5104) without any CSP deviations or dosing 
deviations that might have affected the PK analysis. 
2.2 
Protocol deviations 
Important protocol deviations (or events) include changes to the procedures that may impact 
the quality of data. The following will be considered an important protocol deviation. These 
deviations will be listed and discussed in the CSR as appropriate: 
• Patients entered but who did not receive study treatment (Deviation 1). 
Deviation 1 will lead to exclusion from the safety, PK and PET analysis set. Patients who 
receive the wrong treatment at any time (provided they receive at least 1 administration of 
[11C]osimertinib and/or oral osimertinib) will still be included in the safety analysis set as 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
15 
described in section 2. 
During the study, decisions on how to handle errors in treatment dispensing (with regard to 
continuation/discontinuation of study treatment or, if applicable, analytically) and any other 
important protocol deviation will be made on an individual basis with written instruction from 
the study team leader, appropriate study personnel and/or statistician.  
The important protocol deviations will be listed and summarised across all patients.  
3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Parameters of brain exposure of [11C]osimertinib 
The primary outcome variables describe the distribution of [11C]osimertinib in the whole brain 
using a set of exposure parameters including: 
− 
Cmax,%ID brain 
Maximum radioactivity concentration in brain (%), expressed as 
the percentage of injected radioactivity (calculated as the 
radioactivity concentration in the region of interest multiplied 
with the volume of the region of interest), divided by the 
radioactivity injected, and multiplied by 100 
− 
Cmax,SUV brain 
Maximum radioactivity concentration in brain, expressed as the 
standardized uptake value corresponding to the regional 
radioactivity concentration normalized for injected radioactivity 
and body weight 
− 
Tmax brain 
Time of maximum radioactivity concentration in the brain 
(min), obtained directly from the observed concentration versus 
time data 
− 
AUCbrain 0-90 
Area under the brain radioactivity concentration-time curve 
between 0 and 90 minutes (SUV*min) after injection calculated 
by the linear trapezoidal rule 
− 
AUCblood 0-90 Area under the plasma radioactivity concentration-time curve 
between 0 and 90 minutes (SUV*min) after injection calculated 
by the linear trapezoidal rule 
− 
Kp 
Brain plasma partition coefficient – ratio of radiolabelled drug 
in brain to that in plasma calculated as AUCbrain 0-90/AUCblood 0-90 
− 
VT 
Total distribution volume (ml/cc) quantified using kinetic 
compartment model 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
16 
Radioactivity concentrations (as %ID) for the whole brain, tumour regions and anatomical 
regions will be plotted as time activity curves for individual subjects as well as an overlain 
plot for all subjects with arithmetic mean curve. These figures along with PET images after 
administration of [11C]osimertinib will be prepared by the AZ PET Centre at Karolinska 
Institutet.  
Exposure parameters will be summarised for all subjects in the PET analysis set using 
descriptive statistics. Geometric mean and geometric CV% will not be calculated for Tmax brain. 
A by-subject appendix of individual exposure parameters will be provided. 
Note: Some PET data variables may need to be amended after evaluation of first few patients, 
depending on the emerging data and selection of analysis method (kinetic modelling 
approach). Additionally, the PET team at KI may calculate exposure and/or efficacy 
parameters, other than those listed above. Subsequently, additional listings, summary tables, 
and figures may be added to the planned presentation of data. These modifications will be 
covered in a future SAP amendment when data from first few subjects are available.  
3.2 
PK Variables 
All PK concentrations will be listed. Average of the concentrations between the PET 
measurement will also be summarised. Summary data for patients in the PK analysis set will 
be presented in the table. The following PK parameters will be summarized for patients in the 
PK analysis set. There will be no PK parameters presented for patients after the first dose 
(PET2 day) and only steady state PK parameters (PET3) will be calculated.  
Pharmacokinetic parameters for an individual patient were not included in the summaries if 
the patient missed a single dose within 3 days of the planned PK sampling, received a 
different dose on the PK sampling day or ≥7 days of dosing were missed with <10 days back 
on daily administration before the PK sampling day. This list of patients was provided by the 
pharmacokineticist.  The pre-dose time point on PET3 was also used as the 24 hr time point to 
calculate the AUCss since at the time of PET3, if the patient met the above criteria, 
osimertinib and AZ5104 are expected to be at steady state.  
Osimertinib: Area under the concentration time curve from 0-24 hrs at steady state (AUCss), 
maximum plasma concentration at steady state (Cssmax), time of maximum plasma 
concertation at steady state (Tssmax), apparent clearance at steady state (CLss/F). 
AZ5104: AUCss, Cssmax, Tssmax, AZ5104 AUCss/osimertinib AUCss, AZ5104 
Cssmax/osimertinib Cssmax.  
For PET2, ie, after single dose of osimertinib, no PK parameters will be presented due to 
planned limited sampling and only the concentration data will be listed and summarized.  
Events or changes to procedures that may impact the evaluation of PK data including, but not 
limited to, vomiting following oral dosing occurring within the timeframe of 2 times the 
median tmax, wrong dose administered, patient received a prohibited concomitant medication, 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
17 
sample processing errors that lead to inaccurate bioanalytical results, and incomplete PK 
profile. The final decision on the inclusion of the patient in the PK analysis set will be 
determined by the PK scientist and documented in the CSR. The affected PK data collected 
(as deemed by the study pharmacokineticist) will be excluded from the summaries and 
statistical analyses, but will still be reported in the study result listings. Pharmacokinetic 
parameters for an individual patient may not be included in the summaries if the patient 
missed a single dose within 3 days of the planned PK sampling, received a different dose on 
the PK sampling day or ≥7 days of dosing were missed with <10 days back on daily 
administration before the PK sampling day. This list of patients will be provided by the 
pharmacokineticist.  The pre-dose time point on PET3 may also be used as the 24 hour time 
point to calculate the AUCss as at the time of PET3, if the patient met the above criteria, and 
osimertinib and AZ5104 are expected to be at steady state. 
CSF analysis:  
The CSF concentration will be listed for all patients and summarized for patients in the PK 
analysis set. The CSF to plasma and CSF to free plasma ratio will be listed for all patients and 
summarized for patients in the PK analysis set. The free fraction value to 5.27% free for 
osimertinib and 7.92% for AZ5104 will be used for the free plasma calculation based on the in 
vitro plasma protein binding assessments.  
3.3 
Safety and tolerability variables 
Safety and tolerability will be assessed by: 
− 
Assessment of adverse events (AEs), graded by Common Terminology Criteria 
for Adverse Events (CTCAE) (v4.03) 
− 
Physical examination 
− 
Vital signs (including blood pressure [BP], pulse rate, body temperature, and 
weight) 
− 
Standard 12 lead electrocardiograms (ECGs) 
− 
Evaluation of laboratory parameters (clinical chemistry, coagulation, 
haematology and urine analysis) 
− 
Echocardiogram/multiple gated acquisition scan (MUGA) 
− 
Concomitant medications 
Adverse events will be classified according to the terminology of Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or higher (preferred term and system organ 
class [SOC]).   


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
18 
Adverse events reported before any administration of osimertinib will be listed only and be 
referred to as “pre-treatment”. Similarly, AEs reported before any administration of 
osimertinib that continue after the first administration without worsening will also be 
classified as “pre-treatment”. 
 
A treatment emergent AE (TEAE) will be defined as any AE with start date and time on or 
after the first IV dosing of osimertinib in imaging phase up to 30 days after their last study 
treatment administration or immediately before initiation of any other cancer therapy, 
whichever occurs first.   
 
For laboratory data, vital signs and ECG data, baseline is defined as the latest result obtained 
prior to the first IV dose of osimertinib in the imaging phase.  
For all safety data, an on-treatment period is from after the first IV dose of osimertinib  in the 
imaging phase, up to and including the follow-up visit. 
Patients not participating in the continued access phase or who discontinue treatment during 
the imaging phase will return to the clinic for follow-up assessments 30 days (±7 days) after 
their last administration of osimertinib in the imaging phase. If the patient’s last 
administration of osimertinib is in the continued access phase, the patient will be contacted 30 
days after their last administration of osimertinib to follow up on any existing AEs/SAEs and 
monitor for new AEs/SAEs that may be related to the IP, and record any sudden deaths of 
unknown cause. This follow-up assessment will serve as the end-of study assessment for a 
patient. 
Concomitant medications are those which were taken at any time between first dose of 
osimertinib in the imaging phase and completion of or withdrawal from the study. This 
includes medications which were started before first IV dose of osimertinib in the imaging 
phase, but stopped during the course of study (after first IV dosing date/time) or were ongoing 
at completion of or withdrawal from the study.  
Exposure to [11C]osimertinib will be summarized by number of patients receiving 1, 2 or all 3 
doses. 
Exposure to oral osimertinib, during imaging phase, will be assessed using total exposure time 
and actual exposure time 
− 
Total exposure time (months) will be calculated from the first dose to the last 
dose 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
= ( 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 > 0 𝑚𝑚𝑚𝑚 − 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) +  1
30.4375
 
− 
Actual exposure time (months) will be calculated from first dose to the last 
dose, taking account of dose interruptions. 


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[( ݈ܽݏݐ ݀݋ݏ݁ ݀ܽݐ݁ ݓ݄݁ݎ݁ ݀݋ݏ݁ > 0 ݉݃ െ ݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁) +  1
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Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
21 
4.2 
General variables 
4.2.1 
Study day definitions 
For data summaries, Study Day 1 is defined as the date of first IV microdose administration of 
[11C]osimertinib. For visits (or events) that occur on or after Study Day 1, study day is defined 
as (date of visit [event] – date of first IV microdose administration of [11C]osimertinib + 1). 
For visits (or events) that occur prior to Study Day 1, study day is defined as (date of visit 
[event] – date of first IV microdose administration of [11C]osimertinib). There is no Study Day 
0. 
For listings (such as for AEs) that include the derivation of “days since last dose”, this is 
defined as (event date – date of last dose). Events that occur on the same day as the last dose 
of study drug will therefore be described as occurring zero days from the last dose of study 
drug. 
4.2.2 
Visit windows 
For summaries of vital signs, laboratory data, ECG, etc., assessments will be assigned to 
calculated visit windows (using study day). 
The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarised. Inclusion within the visit window should be based on the actual 
date and not the intended date of the visit. For summaries at a subject level, all values should 
be included, regardless of whether they appear in a corresponding visit based summary, when 
deriving a subject level statistic such as a maximum. 
The windows for the visits following baseline (including scheduled visits) will be constructed 
in such a way that the upper limit of the interval falls half way between the two visits. 
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval). Values from 
scheduled and unscheduled visits will be included. Listings should display all values 
contributing to a time point for a subject; they should also highlight the value for that subject 
that was used in the summary table, wherever feasible. 
For visit-based summaries, if there is more than one value per subject within a visit window 
then the closest to the planned study day value should be summarised, or the earlier in the 
event the values are equidistant from the planned study day. The visit will be missing if no 
assessment was reported within the specified visit window around the planned study day. 
4.2.3 
Handling missing data 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing. 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
22 
4.2.3.1 
Imputation of partial dates 
Concomitant medication and adverse events start dates 
• If year is missing (or completely missing), do not impute 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing), impute as January 1st 
• If year and month are present and day is missing, impute days as first day of the month 
Concomitant medication and adverse events end dates 
• If year is missing (or completely missing), do not impute 
• If (year is present and month and day are missing) or (year and day are present and 
month is missing), impute as December 31st, unless this is after the date of death in 
which case date of death will be used instead 
• If year and month are present and day is missing, impute day as last day of the month, 
unless this is after the date of death in which case date of death will be used instead 
In addition, for AEs and CMs if, for a partial start date, the start date could (when also 
considering the end date) potentially be on the first study medication date, the start date will 
be imputed with the first study medication date to assume a “worst case” scenario; e.g. AE 
from UNK-Feb-2014 to 23-Mar-2014 with first study medication date 21-Feb-2014, then the 
AE start date will be imputed to 21-Feb-2014. 
4.2.4 
Imputation rules for lab values outside of quantification range 
Lab values below the lower limit of quantification (LLoQ) that are reported as “<LLoQ” or 
“≤LLoQ” in the database will be imputed by LLoQ × 0.99 for analysis purposes. The original 
value will be listed. 
Lab values above the upper level of quantification (ULoQ) that are reported as “>LLOQ” or 
“≥ULoQ” in the database will be imputed by ULoQ × 1.01 for analysis purposes. The original 
value will be listed. 
 
4.3 
Analysis methods 
4.3.1 
Screening and demographic measurements 
Disposition of patients 
A summary table will be presented specifying the number of patients enrolled, who received 
treatment, who completed the study, and who terminated prematurely.  Data will be 
summarised across all patients. 
In addition, the number of patients included in safety analysis set as well as important protocol 
deviations will also be summarised within separate tables.  These data will be summarised 
across all patients. 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
23 
Demographic data 
Descriptive statistics will be presented for age, height, weight and BMI, In addition, 
frequencies and percentage of patients will be tabulated for the categorical variables age group 
(< 40, >=40 up to 50, >=50 up to 65, and >=65 years), smoking status (never, former, and 
current), sex and ethnic group.  Data will be summarised across all patients. 
Concomitant medication  
Prior medications, concomitant and post-treatment medications are defined based on imputed 
start and stop dates as follow: 
• Prior medications are those taken prior to study treatment with a stop date prior to the 
date of first IV microdose administration of [11C]osimertinib 
 
• Concomitant medications are those with a stop date on or after the date of first IV 
microdose administration of [11C]osimertinib (and could have started prior to or during 
treatment) 
 
• Post-treatment medications are those with a start date after the date of last IV 
microdose administration of [11C]osimertinib or oral osimertinib, whichever is later 
Concomitant medications will be summarised by the coded terms in separate tables per 
whether the medication is allowed or disallowed based on Appendix C of the clinical study 
protocol.  For inclusion in concomitant medication summaries, incomplete medication start 
and stop dates will be imputed as detailed in Section 4.2.3.1.The number of patients receiving 
a medication will be summarised across all patients. A patient is only counted once even if 
they receive the medication more than once.  For detailed information regarding concomitant 
treatments see Section 7.7 of the protocol.    
Other baseline data 
Other demographic and baseline data will be listed and/or summarised (as appropriate) across 
all patients. These data will include nicotine usage, medical and surgical history, past cancer 
treatments and radiotherapy, performance status, serology, and results from pregnancy test, 
follicle-stimulating hormone assessment, luteinising hormone assessment, and physical 
examination. 
4.3.2 
Important protocol deviations 
Important protocol deviations are described in Section 2.2.  A listing detailing the important 
protocol deviations for each enrolled patients will be presented.  Minor protocol deviations, 
not expected to affect the treatment outcome, will not be included in this listing. 
A table summarizing the important protocol deviations, along with the number and percentage 
of patients overall will be presented (based on the safety analysis set). 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
24 
4.3.3 
Safety parameters 
Safety variables 
All safety analyses will be performed on the safety analysis set. 
Treatment Exposure 
Treatment exposure data will be listed and summarised. Total exposure time and actual 
exposure time will be summarized using descriptive statistics for oral osimertinib exposure 
while frequency count of subjects taking number of doses (1, 2 or 3) will be presented for 
[11C]osimertinib exposure.  
Adverse Events 
All AEs will be listed for each patient, and TEAEs will be summarised. 
The following summary tables will be presented across all patients. 
• 
Summary of number (%) of patients who had at least one AE in any category (Any 
AE, any causally related AE, any AE of CTCAE grade 3 or higher, any causally 
related AE of CTCAE grade 3 or higher, any AE with outcome = death, any 
causally related AE with outcome=death, any SAE (including events with outcome 
= death), any causally related SAE (including events with outcome = death), any 
SAE leading to discontinuation of investigational product (IP ie, osimertinib), any 
causally related SAE leading to discontinuation of IP, any AE leading to 
discontinuation of IP, any causally related AE leading to discontinuation of IP, any 
other significant AE, any other causally related significant AE (OAE). 
• 
Summary of number (%) of patients who had at least 1 AE by system organ class 
and preferred term presented by maximum reported CTCAE grade. 
• 
Summary of number (%) of patients who had at least 1 AE with CTCAE grade 3 or 
higher by system organ class and preferred term. 
• 
Summary of number (%) of patients who died and a listing of deaths. 
• 
A listing of key information for SAEs, and a listing of key information for SAEs 
with outcome other than death will be presented. 
• 
A listing of key information for AEs leading to discontinuation of IP will be 
presented. 
• 
Summary of number (%) of patients who had an AE which started prior to study 
treatment or more than 30 days after last dose of study treatment, by system organ 
class and preferred term.   


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
25 
Clinical laboratory variables (haematology, clinical chemistry, coagulation and urine 
analysis) 
All laboratory safety data, incorporating haematology, clinical chemistry, coagulation and 
urine analysis will be listed for each patient with values outside the standard reference ranges 
indicated in the listings.   
Observed and change from baseline values will be summarised by scheduled time point.  
Vital signs (pulse and BP), body temperature and weight 
Pulse rate, systolic and diastolic BP, body temperature and weight will be listed by patient and 
summarised for observed and change from baseline by scheduled time point. 
Electrocardiogram, physical examination and echocardiogram/MUGA 
Electrocardiogram variables (heart rate, RR, PR, QRS, QT, and QTcF intervals) will be listed 
individually by patient and summarized for observed and change from baseline by scheduled 
time points. QTc outliers are defined as QTcF values following dosing that are greater than 
450 ms or are increases from baseline greater than 30 ms. QTcF outliers will be highlighted in 
the data listings and summarised using the following categories: 
• Values >450 ms, >480 ms, >500 ms 
• Increase from baseline of >30 ms, increase from baseline of >60 ms, increase from 
baseline of >90 ms 
• Values >450 ms and increases of >30 ms, values >500 ms and increases of >60 ms. 
The number and percentage of patients who meet the ECG outlier criteria at any assessment 
post-date of first administration of microdose of [11C]osimertinib will be summarised. 
Overall ECG evaluation will be summarised using shift tables summarising the change from 
baseline to last on-treatment observation across all patients. 
The results of physical examination and echocardiogram conducted during the study will be 
presented in listings. Left Ventricular Ejection Fraction (LVEF) data from echocardiogram 
will be summarised. 
5. 
INTERIM ANALYSES (NOT APPLICABLE) 
No interim analyses are planned. 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
There are no changes in analyses. 


Statistical Analysis Plan  
Study Code D5160C00043 
Edition Number 1.0  
Date 17AUG2018 
26 
7. 
REFERENCES 
CTCAE v4.03 2010 
Common Terminology Criteria for Adverse Events Version 4.03 2010. 
8. 
APPENDIX (NOT APPLICABLE)