A Phase I/II, Single-Arm, Open Label Study to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With Neurofibromatosis Type 1 (NF1) Related Symptomatic, Inoperable Plexiform Neurofibromas (PN) (SPRINKLE)
Phase: PHASE1
Conditions: Neurofibromatosis Type 1
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
Selumetinib
Study Code
D1346C00004
Version
5.0
Date
15 March 2024 
EudraCT / EU 
CT Number
[2020-005608-20 /     
2023-506357-38-00]
A Phase I/II, Single-Arm, Open-label Study to Evaluate the 
Pharmacokinetics, Safety/Tolerability and Efficacy of the 
Selumetinib Granule Formulation in Children Aged ≥ 1 to 
< 7 Years with Neurofibromatosis Type 1 (NF1) Related 
Symptomatic, Inoperable Plexiform Neurofibromas (PN) 
(SPRINKLE)
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): IND 122851; EudraCT: 2020-005608-20; EU CT 
Number: 2023-506357-38-00
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. 
The CSP 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.
Protocol Number: D1346C00004
Redacted for Public Disclosure

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Version Scope: 5.0
Amendment Number: 4.0
Study Intervention: Selumetinib
Brief Title: Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in 
Children aged ≥ 1 to < 7 Years with NF1-related Symptomatic, Inoperable PN (SPRINKLE).
Medical Monitor Name and Contact Information will be provided separately.
Study Phase: Phase I/II
Acronym: SPRINKLE
Pediatric Investigational Plan Number: EMEA-001585-PIP01-13
Study Clinical Lead Name and Contact Information will be provided separately.
International Coordinating Investigator: PPD

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SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
CSP Version 5.0 (Amendment 4.0)
15-Mar-2024
CSP Version 4.0 (Amendment 3.0)
14-Feb-2023
CSP Version 3.0 (Amendment 2.0)
30-Nov-2022
CSP Version 2.0 (Amendment 1.0)
18-Mar-2022
CSP Version 1.0 (Original Protocol)
05-Aug-2021
Amendment 4.0 (15-Mar-2024)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union and in the EU Clinical Trial Regulation Article 2, 2 (13) because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the 
study.
Overall Rationale for the Amendment:
The main purpose of the amendment is to ensure the CSP is aligned and compliant with the 
specifications required by the EU CTR. Clarifications have been made and other 
typographical errors have been corrected.
Summary of Non-substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Section 8.1: 
Administrative and 
General/Baseline 
Procedures
Added this section, although it is blank in 
terms of content
Added to align the section 
numbers with most recent CSP 
template
Section 8.4.9: 
Reporting of Serious 
Adverse Events
Added the following wording “In the 
European Union, the Sponsor will comply 
with safety reporting requirements and 
procedures as de-scribed in the European 
Clinical Trials Regulation (EU) No 536/2014. 
All Suspected Unexpected Serious Adverse 
Reactions (SUSARs) to investigational 
medicinal product will be reported to the 
EudraVigilance database with-in the required 
regulatory timelines.”
Added to align with EU CTR 
transition requirements

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Section 8.4.11.1: 
Timelines
Added this section
Added to align the section 
numbers with most recent CSP 
template
Section 8.4.11.1: 
Timelines
Changed “If an event of medication error, 
drug abuse, or drug misuse occurs during the 
study, then the Investigator or other site 
personnel informs the appropriate 
AstraZeneca representatives within one day” 
to “If an event of medication error, drug 
abuse, or drug misuse occurs during the study, 
then the Investigator or other site personnel 
informs the appropriate AstraZeneca 
representatives within one calendar day”
Added to align with EU CTR 
transition requirements
Appendix A 1: 
Regulatory and Ethical 
Considerations
Updated section regarding “Regulatory 
Reporting Requirements for Serious 
Breaches”
Added to align with EU CTR 
transition requirements
Appendix A 4: Data 
Protection
Added 2 bullet points:
•
The participant’s legally authorised 
representative (parent or guardian) and 
participant (if deemed appropriate as per local 
regulations) must be informed that data will 
be collected only for the business needs. We 
will only collect and use the minimum amount 
of personal data to support our business 
activities and will not make personal data 
available to anyone (including internal staff) 
who is not authorised or does not have a 
business need to know the information. 
•
The participant’s legally authorised 
representative (parent or guardian) and 
participant (if deemed appropriate as per local 
regulations) must be informed that in some 
cases their data may be pseudonymised. The 
General data Protection Regulation (GDPR) 
defines pseudonymisation as the processing of 
personal data in such a way that the personal 
data can no longer be attributed to a specific 
individual without the use of additional 
information, provided that such additional 
information is kept separately and protected 
by technical and organisational measures to 
ensure that the personal data are not attributed 
to an identified or identifiable natural person. 
Added to align with most recent 
CSP template
Appendix A 4: Data 
Protection
Added subsection regarding “Personal Data 
Breaches”
Added to align with EU CTR 
transition requirements

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Appendix A 5: 
Committee Structure 
Added this section, although it is blank in 
terms of content
Added to align the section 
numbers with most recent CSP 
template
Appendix A 6: 
Dissemination of 
Clinical Study Data 
Updated this section to include wording 
around submission to EU CTIS within a year 
from global End of Trial Date. Also added 
www.astrazenecaclinicaltrials.com link and 
https://euclinicaltrials.eu/ link
Added to align with EU CTR 
transition requirements
Appendix A 7: Data 
Quality Assurance
Updated last bullet point to change data 
retention policy from “15 years after study 
completion” to “a minimum of 25 years after 
study archiving”
Added to align with EU CTR 
transition requirements
Appendix B 4: 
Medication Error, Drug 
Abuse and Drug 
Misuse
Updated wording regarding examples of 
Medication Error
Updated to align with EU CTR 
transition requirements
Appendix G: Country 
Specific Requirement
Added this section 
Added to align with EU CTR 
transition requirements
Appendix M: Protocol 
Amendment History
Updated this section to include Amendment 
3.0 changes
Updated this section to include 
Amendment 3.0 changes

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
SUMMARY OF CHANGES TABLE.................................................................................... 3
TABLE OF CONTENTS ...................................................................................................... 6
1
PROTOCOL SUMMARY ................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities ....................................................................................... 21
2
INTRODUCTION............................................................................................ 29
2.1
Study Rationale ................................................................................................ 29
2.2
Background ...................................................................................................... 29
2.3
Benefit/Risk Assessment................................................................................... 32
2.3.1
Risk Assessment ............................................................................................... 32
2.3.2
Benefit Assessment........................................................................................... 35
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 35
3
OBJECTIVES AND ENDPOINTS................................................................... 35
4
STUDY DESIGN ............................................................................................. 39
4.1
Overall Design.................................................................................................. 39
4.1.1
Study Conduct Mitigation during Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health .......................................................... 39
4.1.2
Overall Design.................................................................................................. 39
4.2
Scientific Rationale for Study Design ............................................................... 41
4.3
Justification for Dose........................................................................................ 42
4.4
End-of-Study Definition ................................................................................... 42
5
STUDY POPULATION.................................................................................... 43
5.1
Inclusion Criteria .............................................................................................. 43
5.2
Exclusion Criteria ............................................................................................. 44
5.3
Lifestyle Considerations ................................................................................... 47
5.3.1
Meals and Dietary Restrictions ......................................................................... 47
5.3.2
Activity............................................................................................................. 47
5.4
Screen Failures ................................................................................................. 47
6
STUDY INTERVENTION ............................................................................... 48
6.1
Study Intervention Administered....................................................................... 48
6.1.1
Investigational Product ..................................................................................... 48
6.1.2
Dose-finding Phase........................................................................................... 50
6.1.2.1
Pharmacokinetics and Safety/Tolerability Acceptability Criteria for the 
Dose-finding Phase........................................................................................... 52
6.1.2.2
Definition of an Evaluable Participant for the Dose-finding Phase .................... 53

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6.2
Preparation/Handling/Storage/Accountability ................................................... 53
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 54
6.4
Study Intervention Compliance......................................................................... 55
6.5
Concomitant Therapy........................................................................................ 55
6.6
Dose Modification ............................................................................................ 58
6.7
Continued Access to Study Intervention after the End of the Study ................... 59
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 60
7.1
Discontinuation of Study Intervention............................................................... 60
7.2
Participant Withdrawal from the Study.............................................................. 61
7.3
Lost to Follow-up ............................................................................................. 61
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 62
8.1
Administrative and General/Baseline Procedures.............................................. 62
8.2
Efficacy Assessments........................................................................................ 62
8.2.1
Imaging of the Target PN.................................................................................. 62
8.2.2
Objective Response Rate .................................................................................. 64
8.2.3
................................................................................. 64
8.2.4
........................................................................................ 64
8.2.5
.......................................................................................... 64
8.2.6
.............................................................................................. 65
8.2.7
Clinical Outcome Assessments.......................................................................... 65
8.2.7.1
.................................................................................................... 65
8.2.7.2
............................................. 66
8.2.7.3
............................................ 66
8.2.7.4
.................................................................. 66
8.2.7.5
.......................................................... 67
8.2.7.6
Palatability........................................................................................................ 67
8.2.7.7
Administration of Electronic Questionnaires..................................................... 67
8.3
Safety Assessments........................................................................................... 69
8.3.1
Physical Examination Including 
.............................. 69
8.3.2
Height and Weight ............................................................................................ 69
8.3.3
Vital Signs ........................................................................................................ 70
8.3.4
Electrocardiograms........................................................................................... 70
8.3.5
Echocardiogram................................................................................................ 71
8.3.6
Ophthalmologic Examinations.......................................................................... 71
8.3.7
Knee/Wrist MRI/X-ray ..................................................................................... 72
8.3.8
Performance Status........................................................................................... 72
8.3.9
Clinical Safety Laboratory Assessments............................................................ 72
8.3.10
Other Safety Assessments ................................................................................. 74
8.3.10.1
................................................................................... 74
8.4
Adverse Events and Serious Adverse Events..................................................... 75
8.4.1
Time Period and Frequency for Collecting AE and SAE Information................ 75
8.4.2
Follow-up of AEs and SAEs ............................................................................. 75
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8.4.3
Causality Collection.......................................................................................... 76
8.4.4
Adverse Events Based on Signs and Symptoms ................................................ 77
8.4.5
Adverse Events Based on Examinations and Tests ............................................ 77
8.4.6
Hy’s Law.......................................................................................................... 77
8.4.7
Disease Progression.......................................................................................... 78
8.4.8
Disease under Study.......................................................................................... 78
8.4.9
Reporting of Serious Adverse Events ................................................................ 78
8.4.10
Pregnancy......................................................................................................... 79
8.4.10.1
Maternal Exposure............................................................................................ 79
8.4.10.2
Paternal Exposure............................................................................................. 79
8.4.11
Medication Error, Drug Abuse, and Drug Misuse.............................................. 79
8.4.11.1
Timelines.......................................................................................................... 79
8.4.11.2
Medication Error............................................................................................... 79
8.4.11.3
Drug Abuse....................................................................................................... 79
8.4.11.4
Drug Misuse ..................................................................................................... 80
8.4.12
Medical Device Deficiencies............................................................................. 80
8.4.13
Adverse Events of Special Interest.................................................................... 80
8.5
Overdose .......................................................................................................... 81
8.6
Human Biological Samples............................................................................... 81
8.6.1
Pharmacokinetics.............................................................................................. 81
8.6.1.1
Collection of Samples....................................................................................... 82
8.6.1.2
Determination of Drug Concentration ............................................................... 82
8.6.2
Pharmacodynamics........................................................................................... 83
8.7
Human Biological Sample Biomarkers ............................................................. 83
8.7.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 83
8.7.2
Other Study-related Biomarker Research .......................................................... 83
8.8
Optional Genomics Initiative Sample................................................................ 83
8.9
Health Economics............................................................................................. 84
9
STATISTICAL CONSIDERATIONS................................................................ 84
9.1
Statistical Hypotheses....................................................................................... 84
9.2
Sample Size Determination............................................................................... 84
9.3
Populations for Analyses................................................................................... 85
9.4
Statistical Analyses ........................................................................................... 86
9.4.1
General Considerations..................................................................................... 86
9.4.2
Pharmacokinetic Assessments........................................................................... 87
9.4.2.1
Primary and Secondary Endpoint(s).................................................................. 87
9.4.2.2
Secondary Endpoint(s)...................................................................................... 88
9.4.2.3
Exploratory Analyses........................................................................................ 89
9.4.3
Safety ............................................................................................................... 89
9.4.3.1
Primary Endpoint(s).......................................................................................... 89
9.4.3.2
Exploratory Safety Endpoints ........................................................................... 90
9.4.4
Efficacy Endpoints............................................................................................ 90
9.4.4.1
Secondary Efficacy Endpoint............................................................................ 90
9.4.4.2
Exploratory Efficacy Endpoints ........................................................................ 90

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9.4.5
Other Analyses.................................................................................................. 90
9.5
Interim Analyses............................................................................................... 91
9.6
Data Monitoring Committee ............................................................................. 91
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 91
OVERALL RATIONALE FOR THE ADDENDUM VERSION 6 (GERMANY): ............. 121
11
REFERENCES............................................................................................... 163
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 19
Figure 2
Dose-finding Phase.................................................................................. 20
LIST OF TABLES
Table 1
Sample Size Estimations based on Inter-subject gCV% and Expected 
Differences in AUC0-12 between SPRINKLE and SPRINT studies......... 18
Table 2
Schedule of Activities.............................................................................. 21
Table 3
Schedule of Activities – Safety Follow-up until Participants are aged 5 
Years ....................................................................................................... 28
Table 4
Risk Assessment...................................................................................... 33
Table 5
Objectives and Endpoints......................................................................... 36
Table 6
Investigational Products........................................................................... 48
Table 7
Initial Proposed Granule Formulation Dose Schema for Selumetinib ....... 49
Table 8
Capsule Dose Schema for Selumetinib 25 mg/m2 bid............................... 50
Table 9
Prohibited Medications............................................................................ 57
Table 10
Granule Formulation Dose Modification Procedure based on Initial 
Proposed Granule Dose Schema .............................................................. 59
Table 11
Capsule Dose Modification Procedure ..................................................... 59
Table 12
PedsQL Scales by Age Group.................................................................. 67
Table 13
Laboratory Safety Variables..................................................................... 73
Table 14
Adverse Events of Special Interest........................................................... 80
Table 15
Pharmacokinetic Sampling Schedule ....................................................... 82
Table 16
Pharmacodynamic Sampling Schedule..................................................... 83
Table 17
Sample Size Estimations based on Inter-subject gCV% and Expected 
Differences in AUC0-12 between SPRINKLE and SPRINT studies......... 85

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Table 18
Populations for Analysis .......................................................................... 85
Table F19
Blood Pressure Levels for Children by Age and Height Percentile –
Blood Pressure for Boys ........................................................................ 119
Table F20
Blood Pressure Levels for Children by Age and Height Percentile –
Blood Pressure for Girls......................................................................... 120
Table F21
New York Heart Association Classification ........................................... 120
Table H22
Performance Status Criteria ................................................................... 126
Table I23
Recommended Granule Dosage of Selumetinib for Co-administration 
with Strong or Moderate CYP3A4 and CYP2C19 Inhibitors based on the 
Initial Proposed Granule Dosing Scheme ............................................... 128
Table I24
Recommended Capsule Dosage of Selumetinib for Co-administration 
with Strong or Moderate CYP3A4 and CYP2C19 Inhibitors.................. 128
Table I25
Inhibitors of CYP2C19 or CYP3A4 that AstraZeneca Recommends not 
to be Combined with Selumetinib .......................................................... 129
Table I26
Inducers of CYP3A4 that AstraZeneca Recommends not to be 
Combined with Selumetinib................................................................... 130
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 92
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 100
Appendix C
Handling of Human Biological Samples ................................................ 105
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 107
Appendix E
Guidance for Management of Specific Adverse Events.......................... 111
Appendix F
Blood Pressure....................................................................................... 119
Appendix G
Country-specific Requirements.............................................................. 121
Appendix H
Performance Status Scales ..................................................................... 126
Appendix I
Guidance Regarding Potential Interactions with Concomitant 
Medications ........................................................................................... 127
Appendix J
Clinical Outcome Assessments .............................................................. 132
Appendix K
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 146
Appendix L
Abbreviations ........................................................................................ 149
Appendix M
Protocol Amendment History................................................................. 154

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Phase I/II Single-Arm, Open-Label Study to Evaluate the Pharmacokinetics, 
Safety/Tolerability and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥ 1 
to < 7 Years with Neurofibromatosis Type 1 (NF1) Related Symptomatic, Inoperable 
Plexiform Neurofibromas (PN) (SPRINKLE).
Short Title: 
Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children 
Aged ≥ 1 to < 7 years with NF1-related Symptomatic, Inoperable PN (SPRINKLE).
Rationale:
Selumetinib (capsule formulation) is approved by the FDA for the treatment of paediatric 
patients 2 years of age and older with NF1 who have symptomatic, inoperable PN and a 
Conditional Marketing Authorisation was granted in Europe/EEA for paediatric patients 
3 years of age and older, via the European Centralised Procedure on 17 June 2021. The 
efficacy of selumetinib in the treatment of NF1-related inoperable PN in paediatric 
participants was demonstrated in the SPRINT study; safety data from this study showed that 
selumetinib has a manageable safety profile with favourable tolerability over several years of 
treatment in this population. 
Selumetinib is currently available in a capsule formulation which precludes administration to 
children with a BSA of < 0.55 m2 or very young children who may have difficulty swallowing 
capsules. Therefore, AstraZeneca has developed an alternative age appropriate granule 
formulation of selumetinib for infants and young children aged ≥ 1 to < 7 years which is 
contained within a sprinkle capsule. 
The relative bioavailability of the granule and capsule formulations has been investigated in 
adult healthy male subjects (Study D1532C00089, Study 89); with a geometric mean ratio 
(90% CI) of 0.654 (0.581, 0.736) for dose-normalized Cmax and 0.865 (0.811, 0.922) for 
dose-normalized AUC. The selumetinib content in the granule formulation batch used in 
Study 89 was 
% therefore, when corrected for selumetinib content, the granule AUC was 
only 
% lower compared to capsule. The selumetinib content in the granule formulation 
which will be used in the SPRINKLE study will be approximately 
%.
This study is designed to define a dosing regimen and assess the PK and safety of the granule 
formulation in children aged ≥1 to < 7 years; the study will also include descriptive analyses 
of exploratory efficacy endpoints. Assuming that the AUC for the granule formulation is 
similar to the AUC for the capsule formulation observed in SPRINT, efficacy in children aged 
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≥ 1 year can be extrapolated from the SPRINT study. The study will inform the benefit risk 
profile of the granule formulation in children aged ≥ 1 to < 7 years with NF1-related 
symptomatic, inoperable PN.
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To determine the PK of selumetinib after 
administration of the selumetinib granule 
formulation.
•
Selumetinib AUC0-12 derived after single dose 
administration.
•
To assess the safety and tolerability of the 
selumetinib granule formulation.
•
Safety and tolerability will be evaluated in terms 
of AEs, clinical safety laboratory assessments 
(clinical chemistry, haematology, urinalysis), 
physical examination, weight, vital signs, ECG, 
ECHO, ophthalmologic assessment, knee (or 
wrist) MRI/X-ray, and performance status.
•
Assessments related to AEs will include: 
occurrence/frequency; relationship to study 
intervention; CTCAE grade; seriousness; death; 
AEs leading to discontinuation of study 
intervention; AEs of special interest.
Secondary
•
To assess the palatability of the selumetinib 
granule formulation
•
Palatability will be assessed using the 
parent-reported observer palatability assessment.
•
To further assess the PK of selumetinib and 
N-desmethyl selumetinib metabolite after 
administration of the selumetinib granule 
formulation.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 

Selumetinib AUC0-12 derived after 
multiple dose administration.

Cmax, AUC0-6, AUClast, CL/F, tmax, 
tlast derived after single and multiple dose 
administration.

AUC0-24, Vz/F and t½λz after single dose 
administration.

Rac Cmax, Rac AUC0-12, and Vss/F 
derived after multiple dose administration. 
•
Plasma concentrations and PK parameters of 
N-desmethyl selumetinib including, but not 
limited to:

Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after single and multiple 
dose administration. 

Rac Cmax and Rac AUC0-12 derived after 
multiple dose administration.

Parent-to-metabolite ratio for AUC0-6, 
AUC0-12 and AUC0-24 (single dose 
only), and Cmax after single and multiple 
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Objectives
Endpoints
•
To evaluate the efficacy of the selumetinib 
granule formulation by assessment of ORR as 
determined by ICR per REiNS criteria.
•
Objective Response Rate
Exploratory Objectives
•
To evaluate the efficacy of the selumetinib 
granule formulation by assessment of 
 
 as determined by ICR per 
REiNS criteria.
•
•
•
•
•
To evaluate efficacy of the selumetinib granule 
formulation by assessment of
•
Parent-reported 
 
 total score.
•
To evaluate efficacy of the selumetinib granule 
formulation by assessment of 
 
•
 
 
 
. 
•
To evaluate the safety of the selumetinib 
granule formulation by assessment of 
•
 to assess language, 
motor skills and cognitive functions in 
participants aged < 3.5 years.
•
 to assess language and cognitive 
functions in participants aged ≥3.5 years.
•
 
 to assess motor skills 
in participants aged ≥3.5 years.
•
.
•
To evaluate the pharmacodynamic effect of 
selumetinib in PBMCs.
•
Change from baseline in PD markers which may 
include but may not be limited to pERK
•
To determine the PK of selumetinib and 
N-desmethyl selumetinib after administration of 
the selumetinib capsule formulation.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 
!
Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after multiple dose 
administration.
!
CL/F and VssF derived after multiple dose 
administration. 
•
Plasma concentrations and PK parameters of 
N-desmethyl selumetinib including, but not 
limited to:
!
Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after multiple dose 
administration.
!
Parent to metabolite ratio for AUC0-6, 
AUC0-12, and Cmax after multiple dose 
administration.
•
For the participants that transition to capsule 
formulation, 
 AUC0-6, 
AUC0-12, AUClast and Cmax will be 
determined following multiple dose 
administration of granule and capsule 
formulation. The ratio of granule:capsule 
formulation will be determined for each of these 
parameters.
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Objectives
Endpoints
•
 analyses will be 
completed to investigate the selumetinib 
exposure-response relationship for safety, 
biomarkers and efficacy.
•
 analyses will be completed to 
assess the effect of 
 on 
selumetinib granule and capsule PK, including 
all paediatric PK data available. In addition, if 
data allows, 
 analyses will be 
completed to investigate the selumetinib 
exposure-response relationship for safety, 
biomarkers and efficacy.
•
To explore potential biomarkers in residual PK 
or PD samples, which may influence the 
progression of neurofibromatosis and 
inoperable PNs (and associated clinical 
characteristics) and/or identify participants 
likely to respond to selumetinib or, may be 
surrogate markers of response.
•
Exploratory biomarker analysis that may include 
(but not limited to) change from baseline in the 
expression and activity of neurofibromatosis and 
MEK pathways and/or specific RNA transcripts 
(arrays) as a surrogate for protein expression.
AE, adverse event; AUC, area under the concentration time curve; AUC0-6, area under the concentration-time 
curve from time zero to 6 hours; AUC0-12, area under the concentration-time curve from time zero to 12 hours; 
AUC0-24, area under the concentration-time curve from time zero to 24 hours; AUClast, area under the 
concentration-time curve from time zero to time of last measurable concentration; 
 
; CL/F, apparent total clearance of the drug from 
plasma; Cmax, maximum peak plasma concentration; CTCAE, Common Terminology Criteria For Adverse 
Events; 
; ECG, electrocardiogram; ECHO, 
echocardiogram; 
 
; 
 ICR, independent central review; MEK, mitogen-activated 
protein kinase; MRI, magnetic resonance imaging; ORR, objective response rate; PBMC, peripheral blood 
mononuclear cells; PD, pharmacodynamic; 
; PK, pharmacokinetics; PN, plexiform 
neurofibroma; Rac, relative accumulation ratio; REiNS, Response Evaluation in Neurofibromatosis and 
Schwannomatosis; RNA, ribonucleic acid 
; t½λz, elimination 
half-life; tlast, time to last measurable concentration; tmax, time to maximum concentration; VssF, apparent 
volume of distribution at steady state after non-intravenous administration; Vz/F, apparent volume of distribution 
after non-intravenous administration.
Overall Design:
This is a Phase I/II, single-arm, open-label study in children aged ≥ 1 to < 7 years at study 
entry (date of ICF signature) with a clinical diagnosis of NF1-related symptomatic, inoperable 
PN. The study is designed to evaluate the PK, safety and tolerability of selumetinib given as a 
granule formulation (Figure 1). 
Participants will receive selumetinib for 25 cycles (or until they meet discontinuation criteria). 
Enrolment into the Global Cohorts (Cohorts 1 and 2) will be stratified by age group:
∀
Cohort 1: participants enrolled outside Japan aged between ≥ 4 and < 7 years
∀
Cohort 2: participants enrolled outside Japan aged between ≥ 1 to < 4 years
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In addition to the Global Cohorts, Japanese participants in Japan aged between ≥1 to 
< 7 years with NF1 related symptomatic, inoperable PN will be enrolled into the Japan 
Cohort.
After completion of at least one cycle (28 days) of dosing in 3 evaluable participants in 
Cohort 1, SRC will review the emerging safety and PK data. Providing the single dose PK 
exposure is within the acceptable range and there are no safety concerns as determined by 
SRC then dosing in Cohort 2 will be initiated and additional participants will be dosed in 
Cohort 1 (Figure 2). If the PK exposure is not within the acceptable range, the dose schema 
may be adjusted to ensure that selumetinib exposure is within the range observed in the 
SPRINT study; PK will be assessed against acceptance criteria in an additional 3 evaluable 
cohort 1 participants who received the adjusted dose. Cohort 2 will be initiated once the 
selumetinib granule formulation dose schema is identified for Cohort 1. The physiologically-
based PK model will be updated, if required, based on emerging PK data.
Additional SRC reviews will be held for each of the cohorts following at least one cycle of 
dosing in approximately 6 evaluable participants and again in approximately 10 evaluable 
participants. The SRC will evaluate the PK, safety and tolerability of the granule formulation 
for that dose schema. The Japan Cohort will not participate in the dose-finding phase.
Participants who are aged ≥ 5 years at the end of 25 cycles of selumetinib will be considered 
to have completed the study for data analysis purposes. Participants who terminate treatment 
prior to Cycle 25 will be followed up to collect MRIs performed as standard of care and 
details of NF1-PN treatment information until the time when they would have completed 
25 cycles of treatment, or they commence an alternative systemic NF1-PN treatment, 
whichever is the earliest. Any participant who is aged < 5 years after 25 cycles of selumetinib 
(or when they terminate treatment with selumetinib) will enter a safety follow-up phase. 
Participation in the safety follow-up will continue until they reach the age of 5 years or 
commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants 
can continue to receive selumetinib (capsule or sprinkle capsule) during the safety follow-up 
as long as they are considered to be receiving benefit in the opinion of their Investigator.
Continued Access to Study Intervention after the End of the Study 
The study will remain open until all participants have discontinued study intervention and 
completed their last expected visit/contact.
After the participant’s last visit, AstraZeneca will continue to supply selumetinib to 
participants whilst they are still receiving clinical benefit or until meeting any other 
discontinuation criteria.
AstraZeneca will continue to supply selumetinib in the continued access phase of this study 
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In the event that product development reaches a point where alternative product supply 
options become available, then these alternative product supply options will be discussed by 
AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to transition 
the participant(s) to alternative supply, where possible.
In the event that a roll-over or safety extension study is available at the time of the final data 
cut-off (DCO) and database closure, participant(s) currently receiving treatment with 
selumetinib may then be transitioned to such a study, and the current study may reach its end. 
The roll-over or extension study would ensure treatment continuation with visit assessments 
per its protocol, as applicable. Any participant who would be eligible to move to such a study 
would be given a new informed consent, as applicable.
Disclosure Statement: This is a single group treatment study with one arm that has no 
masking.
Number of Participants:
Global Cohorts (Cohorts 1 and 2)
Approximately 
 participants will be dosed in Cohorts 1 and 2 to achieve 
 evaluable 
participants at the recommended granule formulation dose schema, of whom at least 
participants will be aged ≥ 1 to < 4 years (with at least  aged < 2 years) and at least 
participants will be aged ≥ 4 to < 7 years at enrolment.
Japan Cohort
A minimum of  evaluable Japanese paediatric participants aged ≥1 to < 7 years with NF1 
related symptomatic, inoperable PN will be enrolled and receive treatment in the Japan 
Cohort.
For Global and Japan Cohorts
An evaluable participant for PK and sample size calculations is defined as a participant with a 
PK profile on Day 1 without any important protocol deviations potentially impacting the PK 
results.
Note: “Enrolled” means a participant’s legally authorised representative (parent or guardian) 
and participant’s (if deemed appropriate as per local regulations) agreement to participate in a 
clinical study following completion of the informed consent process. Potential participants 
who are screened for the purpose of determining eligibility for the study, but do not receive 
selumetinib, are considered “screen failures”, unless otherwise specified by the CSP. 
Intervention Group and Duration:
This study consists of a screening period (up to 28 days), a treatment period (25 cycles) and a 
long term safety follow-up for participants until they are 5 years old or commence an 
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alternative systemic NF1-PN treatment, whichever is the earlier. Participants may continue 
treatment with selumetinib throughout the long term safety follow-up as long as they are 
considered to be receiving clinical benefit in the opinion of their Investigator. A safety 
follow-up assessment will be performed 30 days after the last dose of study intervention for all 
study participants.
Selumetinib will be administered using BSA-based dosing. The granule formulation dose 
schema to be used in the study will be established in the dose-finding phase.  
At enrolment participants must have a BSA within the range 0.40 to 1.09 m2; once participants 
attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule 
formulation, if feasible, although all participants must remain on the granule formulation until 
after they have completed their third cycle of treatment. 
Data Monitoring Committee: No
Safety Review Committee: Yes
An SRC will be formed for the dose-finding phase of the study to evaluate the safety, 
tolerability and PK data of the selumetinib granule formulation. Detailed information will be 
provided in the SRC charter. 
Statistical Methods
Sample Size
Global Cohorts (Cohorts 1 and 2)
Approximately 
 participants will be dosed in Cohorts 1 and 2 to achieve 
 evaluable 
participants at the recommended granule formulation dose schema, of whom at least 
participants will be aged ≥ 1 to < 4 years (with at least aged < 2 years) and at least 
participants will be aged ≥4 to < 7 years. A sample size of 
 participants will provide 
reasonable precision to characterise PK and safety.
With a minimum of 
 evaluable participants in each age group and 
 evaluable participants 
in total, the numbers of participants in the 2 age groups will fall between a combination of 
 to a combination of
. With sample sizes of 
 and 
 in an age group, the 
power to show that the
% CI of the AUC0-12 geometric mean falls within the acceptance 
range (
to 
-fold of the SPRINT AUC0-12 geometric mean; FDA Guidance 2014) will be 
90%, 99.9% and > 99.9%, respectively. The power for two age groups falling within the 
acceptance range simultaneously will therefore be 90% × 99.9% ≈90% and 99.9% × 99.9% ≈
99.9% for the 
 combination and 
 combination, respectively. This sample size 
calculation assumes that there is a ± % difference in exposure between the granule and 
capsule formulation and assumes an inter-subject gCV% of 
% (Wang et al 2012). The 
choice of gCV% is based on observations from Study 89 
%) and the SPRINT study (
%).
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In the dose-finding phase of this study, the exposure AUC0-12 will be monitored on an 
ongoing basis. The minimum sample size for each cohort and the study may be re-estimated 
when 
evaluable participants in that cohort have provided acceptable PK exposures. The re-
estimation will use the observed inter-subject gCV%. Table 1 below shows the minimum 
sample sizes required in each age group corresponding to different variability and different 
scenarios.
Table 1
Sample Size Estimations based on Inter-subject gCV% and Expected 
Differences in AUC0-12 between SPRINKLE and SPRINT studies
Inter-subject gCV%
Difference in AUC0-12 between SPRINKLE and SPRINT studies
± 5%
± 10%
± 15%
AUC 0-12, area under the concentration-time curve from time zero to 12 hours; gCV, geometric coefficient of 
variation.
Japan Cohort
In addition to the Global Cohorts (Cohorts 1 and 2), a separate Japan Cohort of a minimum of 
evaluable participants aged ≥1 to < 7 years will be recruited. 
Primary PK Analysis
During the dose-finding period the individual and median AUC0-12 derived from the Global 
Cohorts of participants given the granule formulation will be compared to the AUC0-12 
 
percentile observed in the SPRINT study at 
 mg/m2. If the dose is adjusted, then the 
AUC will be re-assessed at the adjusted dose to confirm with additional participants that 
exposure is within the 
percentile of SPRINT exposure. 
At the final sample size for the recommended dose schema in the Global Cohorts (Cohorts 1 
and 2), the AUC0-12 geometric mean and 
% CI will be determined for each age group and 
overall. If the 
% CI falls within 
% of the geometric mean AUC0-12 observed in 
the pivotal safety and efficacy study, SPRINT, then it will be considered that comparable 
exposure to selumetinib was observed across the age groups.
Box and whisker plots of observed AUC0-12 (and other PK parameters) will be produced for 
comparison to the target range for the capsule formulation determined from SPRINT.
Analysis Sets
∀
All enrolled set: all participants who sign the ICF.
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
Pharmacokinetic analysis set: all participants who receive at least one dose of selumetinib 
and who have at least one post dose quantifiable plasma concentration with no important 
protocol deviations.

Safety analysis set: all participants who receive at least one dose of selumetinib.
Note: The PK data for the Japan Cohort will be summarised separately from the PK data for 
the Global Cohorts.
There will be three analysis time points:
1
Pharmacokinetics, dose-finding and primary safety analysis: A DCO (DCO1) and 
analysis will occur after all participants have had the opportunity to complete 3 cycles of 
treatment. This primary analysis will confirm the recommended granule formulation dose 
schema and assess PK, safety/tolerability, and palatability. The timing of DCO1 may be 
different for the Global Cohorts (Cohorts 1 and 2) from the Japan Cohort, based on their 
date of Last Subject In.
2
Safety and efficacy of the granule formulation: A DCO (DCO2) and analysis will occur 
after all participants in the study (Global and Japan Cohorts) have had the opportunity to 
complete 25 cycles (or terminated selumetinib); this analysis will provide additional PK 
and safety/tolerability data, as well as palatability and efficacy data.
3
Long term safety follow-up for participants until they reach the age of 5 years or 
commence an alternative systemic NF1-PN treatment, whichever is the earlier: A final 
analysis will occur when all participants in the study (Global and Japan Cohorts) have had 
the opportunity to complete their last assessment in the study, including the safety 
follow-up for participants aged < 5 years.
1.2
Schema
Figure 1
Study Design
DCO, data cut-off; NF1, neurofibromatosis type 1; PN, plexiform neurofibroma.
•
Participants aged ≥ 1 to < 7 years with a diagnosis of NF1 with symptomatic inoperable PN
•
Global Cohorts (Cohorts 1 and 2): stratified by age group:
•
Cohort 1: participants enrolled outside Japan aged between ≥ 4 and < 7 years
•
Cohort 2: participants enrolled outside Japan aged between ≥ 1 and < 4 years
•
Japan Cohort: participants residing in Japan aged between ≥ 1 and < 7 years enrolled within 
Japan 
•
DCO (DCO1) and analysis after last participant has completed 3 cycles to confirm initial 
dose and safety (Primary Endpoint)
•
DCO (DCO2) and analysis after last participant has completed 25 cycles to evaluate efficacy 
and safety over longer term treatment
Selumetinib 25 cycles
•
For participants until they reach the age of 5 years 
(completion of study)
•
Participants may continue to receive selumetinib
during the safety follow up
•
Final analysis when the last participant reaches the 
age of 5 years
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Figure 2
Dose-finding Phase
a.
Additional SRC to be held after approximately 10 evaluable participants have completed one cycle of 
dosing to re-evaluate sample size required for the cohort at the recommended granule formulation dose 
schema.
PK, pharmacokinetics; SRC, Safety Review Committee.
3 evaluable 
     participants 
     aged
> 4 years to < 7 years into Cohort 1
3 evaluable participants aged
> 1 year to < 4 years into Cohort 2
PK within predicted exposure 
range after at least 1 cycle of 
selumetinib and no safety 
issues as determined by SRC 
Continue dosing into Cohort 1
SRC to be held after approximately 6 
evaluable participants have completed 
1 cycle of dosing
YES
NO
PK within predicted exposure 
range after at least 1 cycle of 
selumetinib and no safety 
issues as determined by SRC 
Continue dosing into Cohort 2
SRC to be held after approximately 6 
evaluable participants have completed 
1 cycle of dosing
YES
NO
Adjust dose of granules
PK within predicted exposure 
range after at least 1 cycle of 
selumetinib and no safety 
issues as determined by SRC 
Continue dosing into Cohort 1 
a
YES
PK within predicted exposure 
range after at least 1 cycle of 
selumetinib and no safety 
issues as determined by SRC
NO
YES
Continue dosing into Cohort 2
a
NO
Adjust dose of granules

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1.3
Schedule of Activities
Table 2
Schedule of Activities
Procedure
Screen
Intervention Period in Cycles (28-day cycle) a
EoT Safety 
Follow-up 
(30 days 
after last 
dose)
Section
or
Appendix
C1
D1
C1
D15
C2
D1
C3
D1
C4
D1
C5
D1
C7
D1
C9
D1
C11
D1
C13
D1
C17
D1
C19
D1
C21
D1
C25
D1
Day 7 after 
transition 
to capsule 
formulation 
b
EoT c
Weeks
1
3
5
9
13
17
25
33
41
49
65
73
81
97
Window (days)
-28 to -
1
0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 3
± 3
+ 4 to 14
+ 7
+ 7
Informed consent z
X
A 3
Inclusion and exclusion 
criteria
X
5.1, 5.2
Demography
X
5.1, 5.2
Full Physical 
examination including 
standard neurological 
examination 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.1
Abbreviated physical 
examination 
X
X
8.3.1
Height, weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.2
BSA d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.2
Disease
characteristics e
X
Medical history 
X
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Table 2
Schedule of Activities
Procedure
Screen
Intervention Period in Cycles (28-day cycle) a
EoT Safety 
Follow-up 
(30 days 
after last 
dose)
Section
or
Appendix
C1
D1
C1
D15
C2
D1
C3
D1
C4
D1
C5
D1
C7
D1
C9
D1
C11
D1
C13
D1
C17
D1
C19
D1
C21
D1
C25
D1
Day 7 after 
transition 
to capsule 
formulation 
b
EoT c
Weeks
1
3
5
9
13
17
25
33
41
49
65
73
81
97
Window (days)
-28 to -
1
0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 3
± 3
+ 4 to 14
+ 7
+ 7
Clinical safety lab 
assessments f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.9
12-lead ECG
X
X
X
X
X
X
X
X
X
X
8.3.4
Echocardiogram g
X
X
X
X
X
X
X
X
X g
X g
8.3.5
Ophthalmology 
examination h
X
X
X
X
X
X
X
X h
8.3.6
Knee MRI/X-ray 
(Physeal dysplasia) i
X
X
X
8.3.7
Performance 
status f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.8
Urinalysis f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.9
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3.3
PN assessments using 
volumetric MRI j
X
X
X
X
X
X
As per SoC j
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Table 2
Schedule of Activities
Procedure
Screen
Intervention Period in Cycles (28-day cycle) a
EoT Safety 
Follow-up 
(30 days 
after last 
dose)
Section
or
Appendix
C1
D1
C1
D15
C2
D1
C3
D1
C4
D1
C5
D1
C7
D1
C9
D1
C11
D1
C13
D1
C17
D1
C19
D1
C21
D1
C25
D1
Day 7 after 
transition 
to capsule 
formulation 
b
EoT c
Weeks
1
3
5
9
13
17
25
33
41
49
65
73
81
97
Window (days)
-28 to -
1
0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 3
± 3
+ 4 to 14
+ 7
+ 7
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Table 2
Schedule of Activities
Procedure
Screen
Intervention Period in Cycles (28-day cycle) a
EoT Safety 
Follow-up 
(30 days 
after last 
dose)
Section
or
Appendix
C1
D1
C1
D15
C2
D1
C3
D1
C4
D1
C5
D1
C7
D1
C9
D1
C11
D1
C13
D1
C17
D1
C19
D1
C21
D1
C25
D1
Day 7 after 
transition 
to capsule 
formulation 
b
EoT c
Weeks
1
3
5
9
13
17
25
33
41
49
65
73
81
97
Window (days)
-28 to -
1
0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 3
± 3
+ 4 to 14
+ 7
+ 7
Palatability (Observer 
Palatability) s
Twice 
daily 
C1W
1
Twice 
daily 
C7W1
8.2.7.6
Dispense 
medication t
X
X
X
X
X
X
X
X
X
X
X
X
X
6
Return 
medication/compliance 
check 
X
X
X
X
X
X
X
X
X
X
X
X
X
6.2 6.4
Dispense/return ePRO 
device/review ePROs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.4
Daily Drug Diary
=============================== twice daily ==================================
6.4
Review Daily Drug 
Diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.4
Blood for PD 
Biomarkers u
X
8.6.2
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Table 2
Schedule of Activities
Procedure
Screen
Intervention Period in Cycles (28-day cycle) a
EoT Safety 
Follow-up 
(30 days 
after last 
dose)
Section
or
Appendix
C1
D1
C1
D15
C2
D1
C3
D1
C4
D1
C5
D1
C7
D1
C9
D1
C11
D1
C13
D1
C17
D1
C19
D1
C21
D1
C25
D1
Day 7 after 
transition 
to capsule 
formulation 
b
EoT c
Weeks
1
3
5
9
13
17
25
33
41
49
65
73
81
97
Window (days)
-28 to -
1
0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 3
± 3
+ 4 to 14
+ 7
+ 7
PK 
blood samples v, w
X
X
X
X
X
X
8.6.1.1
Adverse Events x
X
===============================================================================
X
8.4
Concomitant 
medication/ procedures 
X
===============================================================================
X
6.5
NF1 treatments y
================= collect for participants who discontinue selumetinib prior to C25 ====================
a.
After 25 cycles (or discontinuation of selumetinib) participants who are aged < 5 years will enter a long term safety follow-up and assessments will be 
performed as per Table 3. After 25 cycles of treatment if participants are > 5 years of age and unable to access commercial supply and are still receiving 
clinical benefit participants may be able to remain on treatment in the study. Assessments will revert to standard of care at the particular site. There will be 
no more data collection except SAE, overdose and pregnancy reporting. All SAEs, overdoses and pregnancies will be reported until 30 days after last dose.
b.
Once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to completely transition to the capsule formulation, if feasible, although 
all participants must remain on the granule formulation until after they have completed their third cycle of treatment.
c.
An EoT visit will be performed for participants who permanently discontinue study intervention for any reason (except for death, lost to follow-up, or 
withdrawal of consent). The EoT visit should be performed as soon as possible after the end of treatment. 
d.
Calculation of BSA should be done at the specified time points but since BSA determines the dose of selumetinib it should also be calculated more 
frequently, as appropriate, depending on the age and growth rate of the child.
e.
Assessment of baseline disease characteristics includes documenting location of the target and non-target PN (if applicable), any PN-related symptoms and 
results of any previous genetic testing for NF1. (Participants recruited under CSP Version 1.0 will have this data entered in the EDC if available 
retrospectively.)

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f.
If clinical safety laboratory assessments, urinalysis and performance status have been done within 14 days of starting study intervention they do not need to 
be repeated on C1D1 if the participant’s condition has not changed. If laboratory procedures were performed for alternate reasons prior to signing consent 
(but within the 28 day screening window), these can be used for screening purposes with consent of the legally authorised representative (parent or 
guardian) of the participant.
g.
The participant should be examined using the same machine and operator throughout the study wherever possible with a ± 7 day window for each 
assessment. If a participant has had an echocardiogram performed within 4 weeks prior to treatment discontinuation, the EoT visit echocardiogram scan is 
not required unless clinically indicated. An echocardiogram should be performed at the 30 day safety FU only in participants who have a drop in LVEF of 
≥10 percentage points from baseline and to below the LLN at the time of selumetinib end of treatment visit, or if clinically indicated. Participants who have 
a drop in LVEF of >10 percentage points from baseline and to below the LLN at the time of selumetinib discontinuation should have a follow-up ECHO, 
ECG, vital signs and weight performed at 30 day safety follow-up.
h.
Assessment window ± 7 days. Ophthalmologic assessments may be performed more often, if clinically indicated, please see Appendix E 3 for more
information. An ophthalmological examination should be performed at the 30 day safety FU only in participants with a retinal abnormality prior to or at 
time of end of treatment visit. 
i.
Where feasible the knee MRI/X-ray will be performed at the same time as the PN volumetric MRI with a ± 7 day window for each assessment. Note that a 
wrist MRI/X-ray is acceptable if it is not possible to perform knee MRI/X-ray. The joint, which is imaged must be consistent throughout the study, except 
occasions where MRI/X-ray of the joint imaged at baseline is not possible. 
j.
Plexiform neurofibroma assessments will be performed at screening and every 4 cycles (16 ± 1 weeks) for the first 13 cycles, and subsequently every 6 
cycles (24 ± 1 weeks). MRI data for participants who discontinue selumetinib prior to C25 will be collected if a suitable MRI is performed as part of SoC 
until the time when they would have completed 25 cycles of treatment, or they commence an alternative systemic NF1-PN treatment, whichever is the 
Twice daily for Cycle 1, Week 1 and Cycle 7, Week 1. If the assessment cannot be done at Cycle 7, Week 1 then it should be performed as soon as possible 
afterwards. The Cycle 7, Week 1 assessments should not be completed if the participants are receiving selumetinib capsules. Additional optional 
assessments of palatability can be performed for 7 days when a participant changes doses due to a change in BSA.
t.
Selumetinib will be dispensed every cycle (every 28 days ± 3 days) until Cycle 13, and subsequently every other cycle (± 3 days). If feasible, site to 
participant transport of study drug will be utilised.
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u.
Samples for pERK inhibition should only be taken in participants weighing ≥27 kg. Samples should be taken pre-dose within 10 minutes prior to dosing, at 
1 and 3 hours post-dose (± 15 minutes), and at 18-24 hours post-dose.
v.
Blood samples to measure selumetinib and N-desmethyl selumetinib metabolite will be collected pre-dose within 10 minutes prior to dosing, and 1, 2, 3, 
and 4 hours post-dose ± 15 minutes; 6 and 8 hours post-dose ± 30 minutes; 10-12, and 18-24 hours after selumetinib single dose on Cycle 1, Day 1 (only 
1 dose will be given on Cycle 1, Day 1); bid continuous dosing will start from Cycle 1, Day 2 and blood samples will be taken pre-dose, 1, 2, 3, 4, 6, 8, and 
10-12 hours post-dose on Cycle 2, Day 1. The Cycle 2, Day 1 12 hour sample should be taken prior to the second dose. At any other visit (as indicated in 
the table), only pre-dose blood sample will be collected. In participants that transition from granule formulation to capsule formulation, blood samples will 
be taken on Day 7 (range Day 4 to 14) pre-dose, 0.5, 1.5, 3, 6, and 10-12 hours post-dose, as long as the participant has received 3 consecutive days of twice 
daily dosing with capsule formulation immediately prior to the PK day.
w.
For operational reasons, the pharmacokinetic sampling on Cycle 2, Day 1 can take place on any day between Cycle 1, Day 24 and Cycle 2, Day 8 as long as 
the participant has received 3 consecutive days of bid dosing immediately prior to the PK day. Every effort should be made to conduct PK sampling within 
the window. However, if for unforeseen reasons this is not possible, PK sampling can be performed at any time from 7 days prior to Cycle 2, Day 1 to the 
end of cycle 3 provided the participant has received 3 consecutive days of dosing immediately prior to the PK day.
x.
Adverse events will be collected from the time of signing the informed consent form, throughout the treatment period, and including the follow-up period.
y.
Other systemic NF1-PN targeted treatments will be collected for all participants who discontinue selumetinib until the time when they would have
completed 25 cycles of treatment, or they commence an alternative systemic NF1-PN treatment whichever is the earliest. 
z.
Consent can be performed on Day -42 onwards. All screening assessments must be performed within 28 days prior to dosing.
; BSA, body surface area; C, cycle; CSP, Clinical Study Protocol; 
D, day; 
; ECG, electrocardiogram; EDC, electronic data capture; EoT, end of treatment; 
 
; FU, follow-up; 
 
 LLN, lower limit of normal; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; NF1, neurofibromatosis 
type 1; PD, pharmacodynamic; 
; PK, pharmacokinetic(s); PN, plexiform neurofibroma; SoC, standard of care; 
VMI, Visual-Motor Integration; W, week.
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Table 3
Schedule of Activities – Safety Follow-up until Participants are aged 5 Years 
Participants receiving selumetinib treatment a
Participants no longer receiving 
selumetinib treatment
Procedure b
Every 6 cycles
Every 12 cycles
EoT Safety Follow-up 
(30 days after last dose)
Every 6 months
Every year
Section or Appendix
Window
± 7 days
± 7 days
+ 7 days
± 7 days
± 7 days
Full Physical examination 
X
X
X
8.3.1
Height, weight
X
X
X
8.3.2
BSA 
X
X
8.3.2
Clinical safety laboratory assessments 
X
X
X
8.3.9
12-lead ECG
X
X
If clinically indicated
8.3.4
Echocardiogram 
Approximately every 3 cycles
X
If clinically indicated
8.3.5
Ophthalmology examination
X
X
If clinically indicated
8.3.6
Knee MRI/X-ray (Physeal dysplasia)
X
X
8.3.7
Performance status
X
X
X
8.3.8
Urinalysis
X
X
X
8.3.9
Vital signs
X
X
X
8.3.3
Dispense medication d
To be dispensed every 2 cycles
6
Return Medication/Compliance Check
===================
X
6.2 6.4
SAEs and AEs causally related to selumetinib
===================
X
=========================
8.4
a.
PN tumour assessment should be continued as standard of care if participants remain on treatment. No information about the MRI will be collected (i.e., not 
date/time of scan or images).
b.
The participant should continue to attend all assessments as described until they are ≥ 5 years of age (assessments should continue until the first visit after 
their 5th birthday) or commence an alternative systemic NF1-PN targeted treatment, whichever is earlier. 
Selumetinib will be dispensed every 2 cycles (± 3 days). If feasible, site to participant transport of study drug will be utilised.
AE, adverse event; BSA, body surface area; ECG, electrocardiogram; EoT, end of treatment; MRI, magnetic resonance imaging; NF1, neurofibromatosis type 1; 
PN, plexiform neurofibroma; SAE, serious adverse event.
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2
INTRODUCTION
2.1
Study Rationale
Selumetinib capsule is approved by the FDA for the treatment of paediatric patients 2 years of 
age and older with NF1 who have symptomatic, inoperable PN and a Conditional Marketing 
Authorisation was granted in Europe/EEA for paediatric patients 3 years of age and older, via 
the European Centralised Procedure on 17 June 2021. The efficacy of selumetinib in the 
treatment of NF1-related inoperable PN in paediatric participants was demonstrated in the 
SPRINT study; safety data from this study showed that selumetinib has a manageable safety 
profile with favourable tolerability over several years of treatment in this population. 
Selumetinib is currently available in a capsule formulation which precludes administration to 
children with a BSA of < 0.55 m2 or very young children who may have difficulty swallowing 
capsules. Therefore, AstraZeneca has developed an alternative age appropriate granule 
formulation of selumetinib for infants and young children aged ≥ 1 to < 7 years which is 
contained within a sprinkle capsule.  
The relative bioavailability of the granule and capsule formulations has been investigated in 
adult healthy male subjects (Study D1532C00089, Study 89); with a geometric mean ratio 
(90% CI) of 0.654 (0.581, 0.736) for dose-normalized Cmax and 0.865 (0.811, 0.922) for 
dose-normalized AUC. The selumetinib content in the granule formulation batch used in 
Study 89 was
% therefore, when corrected for selumetinib content, the granule AUC was 
only 
% lower compared to capsule. The selumetinib content in the granule formulation 
which will be used in the SPRINKLE study will be approximately 
%.
This study is designed to define a dosing regimen and assess the PK and safety of the granule 
formulation; the study will also include descriptive analyses of the exploratory efficacy 
endpoints. Assuming that the AUC in this study is similar to the AUC observed in SPRINT, 
efficacy in children aged ≥ 1 to < 7 years can be extrapolated from the SPRINT study 
(Gross et al 2020). The study will inform the benefit risk profile of the granule formulation in 
children aged ≥ 1 to < 7 years with NF1-related symptomatic, inoperable PN.
2.2
Background
Neurofibromatosis type 1 is an autosomal dominant disorder with an estimated prevalence of 
2.13/10,000 individuals in Europe (OrphaNet Report Services 2020). There are no studies 
estimating the prevalence of NF1 in the US and most authors cite studies conducted in 
Europe. Neurofibromatosis type 1 is characterised by diverse, progressive cutaneous, 
neurological, skeletal, and neoplastic manifestations. Symptoms of NF1 generally manifest 
very early in life and the subsequent increase in morbidity can be severe.
Neurofibromatosis type 1 arises from pathogenic variants of the NF1 gene encoding the 
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tumour suppressor protein neurofibromin, a GTPase-activating protein whose normal function 
is to downregulate RAS activity (Ballester et al 1990, Bollag and McCormick 1991, 
Cawthon et al 1990, Martin et al 1990, Viskochil et al 1990, Wallace et al 1990). Constitutive 
activation of the RAS/RAF/MEK/ERK pathway is implicated in cell proliferation and is 
central to driving cancer growth and progression (Davies et al 2007). Neurofibromin 1 
pathogenic variants lead to a failure to inactivate RAS, and can result in PNs (Basu et al 1992, 
Cichowski et al 2003). Affected individuals start life with one mutated (nonfunctional) copy 
and one functional copy of NF1 in every cell in their body. Although many of the clinical 
features of this syndrome are apparent from birth, complete loss of gene function is needed for 
tumour formation through acquisition of a somatic NF1 mutation in selected cells 
(Gutmann et al 2013, Ruggieri and Packer 2001).
Plexiform neurofibromas develop in 20% to 50% of individuals with NF1. Plexiform 
neurofibromas in NF1 patients are histologically benign Schwann-cell tumours 
(Rutkowski et al 2000, Wu et al 2005) that, depending on the location and the growth rate, 
bear all the characteristics typical of cancers. Most NF1-related PNs are congenital or occur 
very early in life and are characterised by slow growth, complex shape, and sometimes very 
large size (up to 20% of body weight) (Korf 1999, Mautner et al 2008). Growth of PNs occurs 
more rapidly in young children ( Akshintala et al 2020, Nguyen et al 2012, Tucker et al 2009). 
Spontaneous regression of PNs is uncommon and although occasionally seen in adolescents 
and young adults, it was not seen in young children (Akshintala et al 2020, Gross et al 2018). 
Consequently, there is a significant treatment need for young children with NF1-PN. These 
tumours can cause severe morbidity such as pain, neurological dysfunction, and 
disfigurement, and also have the potential to transform to MPNSTs (Nguyen et al 2011, 
Prada et al 2012). The lifetime incidence of MPNSTs in NF1 is 15.8%, and many MPNSTs 
arise in pre-existing PNs (Uusitalo et al 2016); MPNST is a rare disease in the general 
population with a lifetime incidence of 0.001% (Ferrari et al 2007).
Selumetinib (AZD6244, ARRY 142886, AR00142886, AR-142886-X [where X refers to a 
sequential lot number], KOSELUGO®) is an oral, potent, and highly selective, allosteric 
MEK1/2 inhibitor with a short half-life (Banerji et al 2010, Denton and Gustafson 2011). It is 
licensed for development by AstraZeneca Pharmaceuticals from Array BioPharma and is 
being co-developed by AstraZeneca and Merck & Co. Selumetinib can inhibit PN growth by 
blocking RAS signalling ( Gross et al 2018, Gross et al 2020, Weiss et al 1999, 
Widemann et al 2014). 
Analysis of volumetric MRI data by NCI POB central review from a Phase I open-label, 
single-arm, Investigator-sponsored study (Study 8799 [NCI 11-C-0161; SPRINT; 
NCT01362803]) in paediatric patients (aged 3 to 18 years at enrolment) with NF1-related 
inoperable PN demonstrated durable tumour shrinkage with confirmed tumour volume 
decreases of ≥ 20% from baseline (Dombi et al 2016). These observations led to the addition 

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of a Phase II part to the study to further evaluate the effect of selumetinib capsules on tumour 
response, pain, quality of life, and physical functioning in paediatric patients (aged 2 to 
18 years at enrolment) with NF1-related symptomatic inoperable PN. Analysis of volumetric 
MRI data by NCI POB central review from SPRINT Phase II Stratum 1 showed durable 
tumour shrinkage along with clinical benefit (Gross et al 2020). 
The NCI POB central analysis-assessed ORR was 66% (95% CI: 51.2 to 78.8) in the SPRINT 
study. The median time to onset of response was 7.2 months (range 3.3 months to 1.6 years). 
The median DoR from onset of response was not reached; at the time of DCO the median 
follow-up time was 22.1 months. Of the 33 patients who had confirmed PR, 27 (81.8%) 
remained in response after 12 months; the remaining 6 patients were censored and had not 
progressed. The median time from treatment initiation to disease progression while on 
treatment was not reached. At the time of DCO, 28 (56%) patients remained in confirmed PR, 
2 (4%) had unconfirmed PRs, 15 (30%) had stable disease and 3 (6%) had PD. 
Clinical Outcome Assessments were generally improved with an overall reduction in pain, 
improvement in motor function and mobility, improved bowel and bladder function and 
overall improvement in quality of life assessments. Selumetinib showed good tolerability with 
mainly mild or moderate AEs which were manageable long term via supportive therapy and/or 
dose interruption or reduction. 
The safety, tolerability, PK, and efficacy of selumetinib capsules in Japanese paediatric 
patients with NF1 and inoperable and symptomatic PNs is being investigated in the Phase I 
Study D1346C00013 (NCT04495127). An interim data cut-off (DCO1 on 16 June 2021) after 
all 12 patients had reached Cycle 7 Day 1 demonstrated that selumetinib capsule monotherapy 
is well tolerated and has a manageable safety profile in paediatric Japanese patients with 
NF1-related PN. Additionally, the PK profile of selumetinib capsules in Japanese paediatric 
patients appeared to be similar to that observed in the pivotal SPRINT study. Following a 
single 25 mg/m2, selumetinib geometric mean ratio (90% CI) for Cmax and AUC0-12 were 
1.07 (0.79, 1.45) and 1.26 (1.02, 1.55), respectively, for Study 13 compared to SPRINT 
Phase II Stratum 1. Given the considerable overlap of these exposures and that there was no 
clear relationship observed for exposure and safety or efficacy, these differences are not 
considered clinically relevant. There is no dose adjustment required for Japanese patients; the 
recommended dose is 
 mg/m2.
Selumetinib (KOSELUGO®) capsules were approved for the treatment of paediatric patients 
≥2 years of age with NF1 who have symptomatic, inoperable PN in the US on 10 April 2020 
and a Conditional Marketing Authorisation was granted in Europe/EEA for paediatric patients 
3 years of age and older, via the European Centralised Procedure in the EU on 17 June 2021.
A detailed description of the chemistry, pharmacology, efficacy, and safety of selumetinib is 
provided in the Investigator’s Brochure.
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2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
selumetinib may be found in the Investigator’s Brochure.
2.3.1
Risk Assessment
The potential risks associated with selumetinib or with the study procedures are shown in 
Table 4. Guidance and algorithms for the management of these risks are described in 
Appendix E. 

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Table 4
Risk Assessment
Potential risk of clinical 
significance
Rationale for risk
Mitigation strategy
Potential risks associated with selumetinib
Gastrointestinal effects: 
diarrhoea, nausea and 
vomiting
Diarrhoea, nausea and vomiting are reported very commonly, 
mostly Grade 1 or 2 but with some Grade 3 events. SAEs of 
diarrhoea have been reported. In very young children, early 
intervention may be required to prevent dehydration.    
Dose interruptions or modifications to the selumetinib dose.
See Appendix E for management guidelines for diarrhoea. 
Vision blurred
Central Serous Retinopathy 
Retinal Pigment Endothelial
Detachment
Retinal vein occlusion
Blurred vision (Grade 1 or 2) is a common ADR and may 
indicate the early onset of a more serious underlying retinal 
toxicity, although RVO, CSR and RPED have not been seen in 
paediatric patients in the pivotal study. In young children, 
communication of visual disturbance may be difficult, making 
early detection and mitigation more challenging.  
Exclusion of participants with: current or past history of 
CSR; history of RVO; IOP > 21 mmHg; or uncontrolled 
glaucoma (irrespective of IOP). 
An ophthalmologic examination will be evaluated at the 
times outlined in the SoA, and as clinically indicated.
See Appendix E for management guidelines.
Creatine phosphokinase 
increase
CPK increase is a very commonly reported ADR in paediatric 
patients. In paediatric patients, elevated CPK reports have all 
been asymptomatic, largely Grade 1 or 2 but some Grade 3 
events and SAEs have been reported. Although myopathy 
directly associated with CPK elevation, or rhabdomyolysis 
have not been reported in paediatric patients, this is a class 
effect. Detection and management of elevated CPK levels are 
therefore considered important risk mitigation.     
Dose interruptions or modifications to the selumetinib dose. 
See Appendix E for management guidelines.
Rash/dermatitis acneiform.
Rash and dermatitis acneiform are very commonly reported 
ADRs in paediatric patients. The majority are Grade 1 or 2 but 
some Grade 3 events have been reported. Dermatitis acneiform 
has predominantly been reported in post-pubertal children. In 
paediatric patients rash was not considered to be associated 
with skin infection/cellulitis but management according to 
toxicity management guidelines is considered important to 
improve tolerability.
Dose interruptions or modifications to the selumetinib dose. 
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Table 4
Risk Assessment
Potential risk of clinical 
significance
Rationale for risk
Mitigation strategy
Left ventricular ejection 
fraction decreases
Asymptomatic, Grade 1 or 2 LVEF decrease identified on 
routine ECHO are reported as very common ADRs in 
paediatric patients. Although symptomatic LVSD has not been 
reported in paediatrics, routine ECHO is important to detect 
any abnormality especially in very young patients for whom 
detection of symptoms (eg, dyspnoea, oedema, fatigue) may 
be more challenging.  
Exclusion of participants with current unstable or 
uncompensated cardiac conditions or LVEF below LLN. See 
Appendix E for management guidelines.
Physeal dysplasia
Growth plate abnormalities have been seen in a single animal 
species at 11 times the clinical free exposure. This finding has 
also been reported preclinically with other MEK inhibitors. 
This preclinical risk has not been identified clinically 
following longitudinal assessment of height and growth 
velocity in paediatric patients on selumetinib (median total 
duration of exposure 28.1 months). However, there remains a 
potential risk of physeal dysplasia in paediatric patients with 
open growth plates, which could lead to joint pain and limb 
shortening. Routine monitoring during clinical studies is 
therefore required.
The healthcare professionals involved in clinical studies on 
paediatric populations should look for signs of physeal 
dysplasia (eg, joint pain and fatigue after exercising, 
abnormal gait, spine irregularities). Children who show signs 
of physeal dysplasia during treatment may need assessment 
of the knee or wrist joint by X-ray or MRI to assess for 
physical dysplasia. If clinical symptoms are identified at the 
time of selumetinib discontinuation participants should have 
a follow-up assessment after 30 days to evaluate the 
potential for reversibility.
ADR, adverse drug reaction; CPK, creatine phosphokinase; CSR, central serous retinopathy; ECHO, echocardiogram; IOP, intraocular pressure; LLN, lower 
limit of normal; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; MEK, mitogen activated protein kinase; MRI, magnetic 
resonance imaging; RPED, retinal pigment endothelial detachment; RVO, retinal vein occlusion; SAE, serious adverse event; SoA, schedule of activities.

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2.3.2
Benefit Assessment
Selumetinib capsules have been shown to be effective in the treatment of paediatric patients with 
NF1 who have symptomatic, inoperable PN and are approved in the US for the treatment of 
paediatric patients aged ≥2 years of age. In the pivotal SPRINT study, selumetinib showed a 
durable and sustained tumour shrinkage, with an overall response rate of 66%, alongside 
improvement in clinical outcomes (Gross et al 2020). There are no other approved treatments for 
NF1-PN. It has been demonstrated previously that younger NF1-PN patients have faster growing 
PNs (Akshintala et al 2020, Nguyen et al 2012, Tucker et al 2009). An analysis of patient response 
to selumetinib treatment in the SPRINT study by age group shows that there is a numerically higher 
ORR in the youngest age group (≥ 3 to 7 years), although benefit was observed in all ages. 
Therefore, it is likely that the participants in this study might derive clinical benefit from treatment 
with the granule formulation of selumetinib.
As shown from the relative bioavailability study (D1532C00089; Study 89), food is not expected to 
affect the primary PK analysis variable AUC. Without the fasting restrictions, it is intended that the 
granule formulation dosing posology will be more convenient and pragmatic for this younger 
patient group.
Participants in the study may therefore benefit from treatment. Following the end of the study, a 
mechanism will be in place to ensure that participants will be able to continue taking selumetinib as 
long as they derive clinical benefit, as judged by the investigator.
2.3.3
Overall Benefit: Risk Conclusion
The investigation of selumetinib in participants with NF1-related symptomatic, inoperable PN 
appears favourable based upon: the non-clinical safety profile, the available clinical efficacy and 
safety profile, the risk minimisation, and AE management proposals including manageability of 
various toxicities and the lack of effective alternative treatments. 
During SPRINT it has been established that the safety profile of selumetinib is reflective of its 
pharmacological action, with adverse drug reactions that are both monitorable and manageable. The 
majority are mild or moderate in severity, and in many cases resolve without dose modification. 
However, where required, dose interruptions and/or in some cases a dose reduction have shown that 
symptoms are reversible. Serious adverse events and treatment discontinuations due to AEs are low.
Since the young participants in this study may not be able to self-report any toxicities, close 
monitoring has been put in place to ensure early detection of any potential risks. 
Overall, the benefit/risk assessment supports the administration of selumetinib to participants with 
NF1-related symptomatic, inoperable PN.
3
OBJECTIVES AND ENDPOINTS
The objectives and endpoints of the study are shown in Table 5.

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Table 5
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To determine the PK of selumetinib after 
administration of the selumetinib granule 
formulation.
•
Selumetinib AUC0-12 derived after single dose 
administration.
•
To assess the safety and tolerability of the 
selumetinib granule formulation.
•
Safety and tolerability will be evaluated in terms 
of AEs, clinical safety laboratory assessments 
(clinical chemistry, haematology, urinalysis), 
physical examination, weight, vital signs, ECG, 
ECHO, ophthalmologic assessment, knee (or 
wrist) MRI/X-ray, and performance status.
•
Assessments related to AEs will include: 
occurrence/frequency; relationship to study 
intervention; CTCAE grade; seriousness; death; 
AEs leading to discontinuation of study 
intervention; AEs of special interest.
Secondary
•
To assess the palatability of the selumetinib 
granule formulation
•
Palatability will be assessed using the 
parent-reported observer palatability assessment.
•
To further assess the PK of selumetinib and 
N-desmethyl selumetinib metabolite after 
administration of the selumetinib granule 
formulation.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 

Selumetinib AUC0-12 derived after 
multiple dose administration.

Cmax, AUC0-6, AUClast, CL/F, tmax, 
tlast derived after single and multiple dose 
administration.

AUC0-24, Vz/F and t½λz after single dose 
administration.

Rac Cmax, Rac AUC0-12, and Vss/F 
derived after multiple dose administration. 
•
Plasma concentrations and PK parameters of 
N-desmethyl selumetinib including, but not 
limited to:

Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after single and multiple 
dose administration. 

Rac Cmax and Rac AUC0-12 derived after 
multiple dose administration.
•
Parent-to-metabolite ratio for AUC0-6, 
AUC0-12 and AUC0-24 (single dose only), and 
Cmax after single and multiple dose 
administration.
•
To evaluate the efficacy of the selumetinib 
granule formulation by assessment of ORR as 
determined by ICR per REiNS criteria.
•
Objective Response Rate

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Table 5
Objectives and Endpoints
Objectives
Endpoints
Exploratory Objectives
•
To evaluate the efficacy of the selumetinib 
granule formulation by assessment of 
 
 as determined by ICR per 
REiNS criteria.
•
•
•
•
•
To evaluate efficacy of the selumetinib granule 
formulation by assessment of 
•
Parent-reported 
 
 total score.
•
To evaluate efficacy of the selumetinib granule 
formulation by assessment of 
 
.
•
 
 
 
•
To evaluate the safety of the selumetinib 
granule formulation by assessment of 
•
 to assess language, 
motor skills and cognitive functions in 
participants aged < 3.5 years.
•
 to assess language and cognitive 
functions in participants aged ≥3.5 years.
•
 
to assess motor skills 
in participants aged ≥3.5 years.
•
.
•
To evaluate the pharmacodynamic effect of 
selumetinib in PBMCs.
•
Change from baseline in PD markers which may 
include but may not be limited to pERK
•
To determine the PK of selumetinib and 
N-desmethyl selumetinib after administration of 
the selumetinib capsule formulation.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 
!
Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after multiple dose 
administration.
!
CL/F and VssF derived after multiple dose 
administration. 
•
Plasma concentrations and PK parameters of 
N-desmethyl selumetinib including, but not 
limited to:
!
Cmax, AUC0-6, AUC0-12, AUClast, 
tmax, tlast derived after multiple dose 
administration.
!
Parent to metabolite ratio for AUC0-6, 
AUC0-12, and Cmax after multiple dose 
administration.
•
For the participants that transition to capsule 
formulation, 
 AUC0-6, 
AUC0-12, AUClast and Cmax will be 
determined following multiple dose 
administration of granule and capsule 
formulation. The ratio of granule:capsule 
formulation will be determined for each of these 
parameters.
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Table 5
Objectives and Endpoints
Objectives
Endpoints
•
 analyses will be 
completed to investigate the selumetinib 
exposure-response relationship for safety, 
biomarkers and efficacy.
•
 analyses will be completed to 
assess the effect of 
 on 
selumetinib granule and capsule PK, including 
all paediatric PK data available. In addition, if 
data allows, 
 analyses will be 
completed to investigate the selumetinib 
exposure-response relationship for safety, 
biomarkers and efficacy.
•
To explore potential biomarkers in residual PK 
or PD samples, which may influence the 
progression of neurofibromatosis and 
inoperable PNs (and associated clinical 
characteristics) and/or identify participants 
likely to respond to selumetinib or, may be 
surrogate markers of response.
•
Exploratory biomarker analysis that may include 
(but not limited to) change from baseline in the 
expression and activity of neurofibromatosis and 
MEK pathways and/or specific RNA transcripts 
(arrays) as a surrogate for protein expression.
AE, adverse event; AUC, area under the concentration time curve; AUC0-6, area under the concentration-time curve 
from time zero to 6 hours; AUC0-12, area under the concentration-time curve from time zero to 12 hours; AUC0-24, 
area under the concentration-time curve from time zero to 24 hours; AUClast, area under the concentration-time curve 
from time zero to time of last measurable concentration; 
 
 CL/F, apparent total clearance of the drug from plasma; Cmax, maximum peak plasma 
concentration; CTCAE, Common Terminology Criteria For Adverse Events; 
, 
; ECG, electrocardiogram; ECHO, echocardiogram; 
 
 
ICR, independent 
central review; MEK, mitogen-activated protein kinase; MRI, magnetic resonance imaging; ORR, objective response 
rate; PBMC, peripheral blood mononuclear cells; PD, pharmacodynamic; 
; PK, 
pharmacokinetics; PN, plexiform neurofibroma; Rac, relative accumulation ratio; REiNS, Response Evaluation in 
Neurofibromatosis and Schwannomatosis; RNA, ribonucleic acid; 
 
t½λz, elimination half-life; tlast, time to last measurable concentration; tmax, time to maximum concentration; VssF, 
apparent volume of distribution at steady state after non-intravenous administration; Vz/F, apparent volume of 
distribution after non-intravenous administration.
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4
STUDY DESIGN
4.1
Overall Design
4.1.1
Study Conduct Mitigation during Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health
The guidance given below supersedes instructions provided elsewhere in this CSP and should be 
implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, during 
quarantines and resulting site closures, regional travel restrictions, and considerations if site 
personnel or study participants become infected with SARS-CoV-2 or similar pandemic infection) 
which would prevent the conduct of study-related activities at study sites, thereby compromising the 
study site staff or the participant’s ability to conduct the study. The Investigator or designee should 
contact the study Sponsor to discuss whether the mitigation plans below should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain compliance 
with GCP, and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines (eg, 
hospital policies) or local government, these changes may include the following options: 

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the study 
site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to participate 
in the clinical study can be performed in previously screened participants. The Investigator 
should confirm this with the designated Medical Monitor.

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the participants using telecommunications technology 
including phone calls, virtual or video visits, and mobile health devices.

Home delivery of selumetinib by a designated courier. If a site visit is not possible, selumetinib 
may be delivered to the participant's home by a designated courier if feasible. The option of 
home delivery ensures a participant’s safety in cases of a pandemic where participants may be 
at increased risk by travelling to the site/clinic. This will also minimize interruption of 
selumetinib administration during other study disruptions, eg, site closures due to natural 
disaster.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, refer 
to Appendix K. 
4.1.2
Overall Design
This is a Phase I/II, single-arm, open-label study in children aged ≥ 1 to < 7 years at study entry 
(date of ICF signature) with a clinical diagnosis of NF1-related symptomatic, inoperable PN. The 

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study is designed to evaluate the PK, safety and tolerability of selumetinib given as a granule 
formulation. 
Participants will receive selumetinib for 25 cycles (or until they meet discontinuation criteria). 
Enrolment into the Global Cohorts (Cohorts 1 and 2) will be stratified by age group:

Cohort 1: participants enrolled outside Japan aged between ≥ 4 and < 7 years

Cohort 2: participants enrolled outside Japan aged between ≥ 1 to < 4 years
After completion of at least one cycle (28 days) of dosing in 3 evaluable participants in Cohort 1, 
SRC will review the emerging safety and PK data. Providing the single dose PK exposure is within 
the acceptable range and there are no safety concerns as determined by SRC then dosing in Cohort 
2 will be initiated and additional participants will be dosed in Cohort 1. If the PK exposure is not 
within the acceptable range, the dose may be adjusted to ensure that selumetinib exposure is within 
the range observed in the SPRINT study; PK will be assessed against acceptance criteria in an 
additional 3 evaluable cohort 1 participants who received the adjusted dose. Cohort 2 will be 
initiated once the selumetinib granule formulation dose schema is identified for Cohort 1. The 
physiologically-based PK model will be updated, if required, based on emerging PK data.
Additional SRC reviews will be held for each of the cohorts following at least one cycle of dosing 
in approximately 6 evaluable participants and again in approximately 10 evaluable participants. The 
SRC will evaluate the PK, safety and tolerability of the granule formulation for that dose schema. 
The Japan cohort will not participate in dose-finding phase. Further information on the SRC can be 
found in Section 9.6.In addition to the Global Cohorts, Japanese participants in Japan aged between 
≥1 to < 7 years with NF1 related symptomatic, inoperable PN will be enrolled into the Japan 
Cohort.
At enrolment participants must have a BSA within the range 0.40 to 1.09 m2; once participants 
attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule 
formulation, if feasible, although all participants must remain on the granule formulation until after 
they have completed their third cycle of treatment. 
Participants who are aged ≥ 5 years at the end of 25 cycles of selumetinib will be considered to 
have completed the study for data analysis purposes. Participants who terminate treatment prior to 
Cycle 25 will be followed up to collect MRIs performed as standard of care, and details of NF1-PN 
treatment information until the time when they would have completed 25 cycles of treatment, or 
they commence an alternative systemic NF1-PN treatment, whichever is the earliest. Any 
participant who is aged < 5 years after 25 cycles of selumetinib (or when they terminate treatment 
with selumetinib) will enter a safety follow-up phase until they reach the age of 5 years or 
commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants can 
continue to receive selumetinib (capsule or granule formulations) during the safety follow-up as 
long as they are considered to be receiving benefit in the opinion of their Investigator. The safety 
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years of age when they commence selumetinib as there are no long term safety data currently 
available for patients who received selumetinib at this age.
Continued Access to Study Intervention after the End of the Study 
After the participant’s last visit, AstraZeneca will continue to supply selumetinib to participants 
whilst they are still receiving clinical benefit as outlined in Section 6.7 or until meeting any other 
discontinuation criteria as defined in Section 7.1. 
4.2
Scientific Rationale for Study Design
The efficacy of selumetinib capsule in the treatment of NF1-related symptomatic, inoperable PN in 
paediatric participants was demonstrated in the SPRINT study in which selumetinib was taken bid 
under fasted conditions (fast for 2 hours before each dose and one hour after each dose). Safety data 
from this study showed that selumetinib has a generally predictable and manageable safety profile 
in this population. Study D1346C00013 (NCT04495127) demonstrated selumetinib capsule 
monotherapy is well tolerated and has a manageable safety profile in all 
paediatric Japanese 
patients with NF1-related PN, and that the PK profile appeared to be similar to that observed in the 
pivotal SPRINT study. Following a single 
mg/m2, selumetinib geometric mean ratio (90% CI) 
for Cmax and AUC0-12 were 
and 
 respectively, for Study 13 
compared to SPRINT Phase II Stratum 1. Given the considerable overlap of these exposures and 
that there was no clear relationship observed for exposure and safety or efficacy, these differences 
are not considered clinically relevant. There is no dose adjustment required for Japanese patients; 
the recommended dose is 
mg/m2.
Selumetinib is currently available in a capsule formulation which precludes administration to 
children with a BSA of < 0.55 m2 or very young children who may have difficulty swallowing 
capsules. Therefore, AstraZeneca has developed an alternative age appropriate granule formulation 
of selumetinib for infants and young children aged ≥ 1 to < 7 years which is contained within a 
sprinkle capsule. 
A relative bioavailability study (D1532C00089; Study 89) has been conducted in healthy adult 
volunteers with both selumetinib commercial capsule formulation and the granule formulation; both 
formulations were considered to have a similar extent of exposure (AUC) with a geometric mean 
ratio (90% CI) of 0.86 (0.81, 0.92). (AstraZeneca notes the selumetinib content for the granule 
formulation batch used in Study 89 was 
% and would contribute to the lower exposure 
determined for the granule, whereas the selumetinib content in the current study is expected to be 
close to 
%.) In addition, the effect of a low-fat meal on the granule formulation was 
investigated; no food effect was observed on the overall extent of exposure (AUC) with a geometric 
mean ratio (90% CI) of 0.97 (0.91, 1.02).
This study is designed to define a dosing regimen and assess the PK and safety of the granule 
formulation in children aged ≥ 1 to < 7 years with NF1-related symptomatic, inoperable PN; the 
study will also include descriptive analyses of exploratory efficacy endpoints. It is anticipated that 
efficacy in children aged ≥ 1 year can be extrapolated from the SPRINT study assuming that the 
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AUC for the granule formulation is similar to the AUC for the capsule formulation observed in 
SPRINT. The study will inform the benefit risk profile of the granule formulation in children aged ≥ 
1 to < 7 years with NF1-related symptomatic, inoperable PN.
The safety measures chosen and the PK parameters to be assessed are standard for a Phase I/II study 
of this type.
4.3
Justification for Dose
The approved capsule dose of selumetinib for the treatment of NF1-related symptomatic, inoperable 
PN in paediatric patients 2 years of age and older is 
mg/m2 bid. 
In this study the selumetinib granule formulation will be administered using BSA-based dosing. The 
modelling predictions suggest 
mg bid for children with BSA of 0.40 to 0.49, 0.50 
to 0.59, and 0.60 to 0.69 m2, respectively, to achieve the equivalent exposure of up to 
mg/m2 bid 
in participants with BSA ≥ 0.70 m2; the modelling accounts for possible age related changes in, for 
example, absorption and metabolism (CYP enzymes maturation processes) in children under 3 years 
old. For participants with a BSA 0.7 m2 and above, dosing recommendations with the granule 
formulation are 
with dosing recommendations for selumetinib commercial capsule 
formulation.
The initial proposed selumetinib granule formulation dose schema is based upon physiologically 
based PK simulations. Emerging PK data will be assessed and the selumetinib dose schema may be 
adjusted to ensure exposure to selumetinib is within the range observed in the SPRINT study (see 
Section 6.1.2). The physiologically-based PK model will be updated, if required, based on emerging 
PK data and the initial proposed dose schema may be adjusted.
4.4
End-of-Study Definition
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs under 
FDA and EU regulatory requirements:
∀
European Union requirements define study completion as the last visit of the last participant for 
any protocol related activity.
∀
Food and Drug Administration requirements defines 2 completion dates:
# Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes.
# Study Completion Date – is defined as the date the final participant is examined or receives 
an intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (for example, last participant’s last visit), whether the clinical 
study concludes according to the pre-specified protocol or is terminated.
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A participant is considered to have completed the study if they have completed all phases of the 
study including their last scheduled procedure at their last visit or contact. 
The study may be stopped if, in the judgement of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
See Section 6.7 for details on participant management following the final DCO as well as following 
study completion.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Male and female participants aged ≥1 to < 7 years of age at the time their legally authorised 
representative (parent or guardian) signs the informed consent.
Type of Participant and Disease Characteristics
2
All participants must have a diagnosis of NF1 with symptomatic inoperable PN where:
(a) Participants must have PN and at least one other diagnostic criterion for NF1 
(Legius 2021)

Six or more café-au-lait macules (> 5 mm in greatest diameter in prepubertal 
participants and > 15 mm in greatest diameter in post pubertal participants)

Freckling in the axillary or inguinal region

Optic pathway glioma

Two or more iris Lisch nodules identified by slit lamp examination or two or more 
choroidal abnormalities defined as bright, patchy nodules imaged by optical coherence 
tomography/near-infrared reflectance imaging

A distinctive osseous lesion such as: Sphenoid wing dysplasia, anterolateral bowing of 
the tibia or pseudoarthrosis of a long bone (Note: Sphenoid wing dysplasia is not a
separate criterion in case of an ipsilateral orbital plexiform neurofibroma)

A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in 
apparently normal tissue such as white blood cells

A parent with NF1 who meets the diagnostic criteria above
(b) A PN is defined as a neurofibroma that has grown along the length of a nerve and may 
involve multiple fascicles and branches. A spinal PN involves two or more levels with 

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connection between the levels or extending laterally along the nerve. A histologic 
confirmation of the PN is not necessary in the presence of consistent clinical and 
radiographic findings, but should be considered if malignant transformation of a PN is 
clinically suspected.
(c) Inoperable is defined as a PN that cannot be completely surgically removed without a risk 
of substantial morbidity due to encasement of, or close proximity to, vital structures, 
invasiveness, or high vascularity of the PN; or unacceptable risk from the general 
anaesthetic as assessed by the Investigator
(d) Symptomatic is defined as clinically significant symptoms or complications caused by the 
PN, as judged by the investigator; symptoms may include, but are not limited to, pain, 
motor dysfunction and disfigurement (examples of complications include PN displacing
trachea, or PN causing bladder obstruction and hydronephrosis).
3
Participants must have at least one measurable PN, defined as a PN of at least 3 cm measured 
in one dimension, which can be seen on at least 3 imaging slices and have a reasonably well-
defined contour. Participants who have undergone surgery for resection of a PN are eligible 
provided the PN was incompletely resected and is measurable. The target PN will be defined as 
the clinically most relevant PN, which is symptomatic, inoperable and measurable by 
volumetric MRI analysis. 
4
Performance status: Participants must have a Lansky performance of ≥70 except in participants 
who are wheelchair bound or have limited mobility secondary to a need for mechanical 
breathing support (such as an airway PN requiring tracheostomy or continuous positive airway 
pressure) who must have a Lansky performance of ≥ 40 (Appendix H).
5
Participants must have a BSA ≥ 0.4 and ≤1.09 m2 at study entry (date of ICF signature).
Informed Consent
6
Mandatory provision of consent for the study signed and dated by a participant’s legally 
authorised representative (parent or guardian) along with the paediatric assent form, when 
applicable as described in Appendix A which includes compliance with the requirements and 
restrictions listed in the ICF and in this CSP.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Participants with confirmed or suspected malignant glioma or MPNST. Participants with low 
grade glioma (including optic glioma) not requiring systemic therapy are permitted.
2
History of malignancy except for malignancy treatment with curative intent with no known 
active disease ≥2 years before the first dose of study intervention and of low potential risk of 
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3
Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the 
formulated product, or previous significant bowel resection that would preclude adequate 
absorption, distribution, metabolism, or excretion of selumetinib.
4
A life-threatening illness, medical condition, organ system dysfunction or laboratory finding 
which, in the Investigator's opinion, could compromise the participant's safety, interfere with 
the absorption or metabolism of selumetinib, or put the study outcomes at undue risk.
5
Participants with clinically significant cardiovascular disease as defined by the following: 

Known inherited coronary disease

History of angina or acute coronary syndrome

Symptomatic heart failure - New York Heart Association Class II to IV

Prior or current cardiomyopathy

Severe valvular heart disease

Current or history of atrial fibrillation

Baseline LVEF below LLN or < 55% measured by ECHO

A QTcF > 450 ms

Blood pressure > 95% percentile for age, height and gender measured as described in 
Appendix F.
6
As judged by the Investigator, any evidence of disease (such as severe or uncontrolled systemic 
disease, known moderate or severe hepatic impairment, active infection, active bleeding 
diatheses, or renal transplant), including any participant known to have hepatitis B, hepatitis C, 
or HIV which, in the Investigator's opinion, makes it undesirable for the participant to take part 
in the study. 
7
Liver function tests: 

Total bilirubin > 1.5 × the ULN for age with the exception of those with Gilbert syndrome 
(≥3 × ULN)

AST/ALT > 2 × ULN.
8
Renal Function: 

Creatinine clearance or radioisotope glomerular filtration rate < 60 mL/min/1.73 m2.

Serum creatinine > 0.8 mg/dL (for participants aged ≥1 to < 4 years) or > 1.0 mg/dL (for 
participants aged ≥4 years).
9
Participants with the following ophthalmological findings/conditions:

Current or past history of RPED/CSR or RVO;

Intraocular pressure > 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma 
(irrespective of IOP). Participants with known glaucoma that is clinically pain-free, has no 
clinically meaningful vision (light perception only or no light perception) and has 
increased IOP may be permitted.

Participants with any other significant abnormality on ophthalmic examination should be 
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
Ophthalmological findings secondary to long-standing optic pathway glioma (such as 
visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal PN (such as
visual loss, strabismus) will NOT be considered a significant abnormality for the purposes 
of the study.
10 Have any unresolved chronic toxicity with CTCAE Grade ≥2 which are associated with 
previous therapy for NF1-PN (except hair changes such as alopecia or hair lightening) 
11 Participants who have previously been treated with a MEKi (including selumetinib) and have 
had disease progression, or due to toxicity have either discontinued treatment and/or required a 
dose reduction.
12 Have had major surgery within 4 weeks of the first dose of study intervention, with the 
exception of surgical placement for vascular access. Have planned major surgery during the 
treatment period. 
13 Have inadequate haematological function defined as:

An absolute neutrophil count < 1500/μL

Haemoglobin < 9g/dL

Platelets < 100,000/μL

Have had a transfusion (of red cells or other blood derived products) within the 28 days 
prior to study entry (date of ICF signature).
Prior/Concomitant Therapy
14 Have received or are receiving an IMP or other systemic NF1-PN target treatment (including 
MEKi) within 4 weeks prior to the first dose of study intervention, or within a period during 
which the IMP or systemic PN target treatment has not been cleared from the body (eg, a 
period of 5 'half-lives'), whichever is longer.
15 Has received radiotherapy in the 6 weeks prior to start of study intervention or any prior 
radiotherapy directed at the target or non-target PN.
16 Has received growth factors in the 7 days prior to study entry (date of ICF signature).
17 Receiving herbal supplements or medications known to be strong or moderate inhibitors of the 
CYP3A4 and CYP2C19 enzymes or inducers of the CYP3A4 enzyme unless such products can 
be safely discontinued at least 14 days or 5 half-lives (whichever is longer) before the first dose 
of study medication.
Prior/Concurrent Clinical Study Experience
18 Participation in another clinical study with an investigational product administered in the 30 
days prior to the first dose of study intervention.
19 Known severe hypersensitivity to selumetinib or any excipient in the selumetinib formulation, 
or history of allergic reactions attributed to compounds of similar chemical or biologic 
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Diagnostic Assessments
20 Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or 
orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
Other Exclusions
21 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
22 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements
23 Previous treatment in the present study. 
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
See Section 6.1.1 for details of food and drink restrictions prior to dosing or prior to PK sampling.
Participants should refrain from consumption of Seville oranges, grapefruit, or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the start of study 
intervention until after the final dose. 
5.3.2
Activity
Participants/parents/guardians should be made aware of the need for good oral care during studies 
with selumetinib (Appendix E 7).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are not 
subsequently dosed with the study drug. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE.
Participants may be rescreened once if the screening failure was due to a temporary condition. Any 
rescreening of participants must be done in consultation with the AstraZeneca Medical Monitor and 
any decision must be captured in the participant’s medical notes.
Rescreened participants should be assigned the same participant number as for the initial screening. 
Participants should be rescreened once sufficient time has elapsed to feasibly allow correction of the 
reason for screen failure. All assessments must be repeated for rescreening unless they are within 28 
days of starting the first study intervention.
However, rescreening should be documented so that its effect on study results, if any, can be 
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“eligibility criteria not fulfilled” (i.e., participant does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (i.e., participants who are 
not dosed with the IP). 
Participant enrolment is described in Section 6.3.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s) or placebo 
intended to be administered to or medical device(s) utilised by a study participant according to the 
CSP.
6.1
Study Intervention Administered
6.1.1
Investigational Product
Details of the study intervention, selumetinib, are provided in Table 6.
Table 6
Investigational Products
Intervention name
Selumetinib
Selumetinib
Type 
Drug
Drug
Dose formulation
Granule
Capsule
Unit dose strength(s)
mg and 
mg granule formulation in 
sprinkle capsules
mg and 
mg capsules
Dosage level(s)
Depends on outcome of dose-finding 
phase. (See Section 6.1.2)
mg/m2 bid (12 hours apart)
Route of administration
Oral
Oral
Use
Experimental
Experimental
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and labelling
Study intervention will be supplied as
mg (white/white) and 
mg 
(white/blue) sprinkle capsules in 
 
count bottles. Each bottle will be 
labelled in accordance with Good 
Manufacturing Practice Annex 13 and 
per country regulatory requirement. 
Labels will be prepared in accordance 
with GCP Ordinance.  
Study intervention will be supplied as 
 mg (white) and 
mg (blue) 
capsules in 
 count bottles. Each bottle 
will be labelled in accordance with 
Good Manufacturing Practice Annex 13 
and per country regulatory requirement. 
Labels will be prepared in accordance 
with GCP Ordinance.
[Current/former name(s) or 
alias(es)]
AZD6244
KOSELUGO®
AZD6244
KOSELUGO®
bid, twice daily; GCP, Good Clinical Practice; IMP, investigational medicinal product; NIMP, non-investigational 
medicinal product. 
The initial proposed dose schema for the selumetinib granule formulation is shown in Table 7. Body 
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surface area will be calculated on Cycle 1, Day 1 and at intervals as shown in the SoA or more 
frequently, as appropriate, and the dosing regimen adjusted as needed. For participants with BSA in 
the range of 0.40 to 0.69 m2 the proposed dose is expected to achieve the equivalent exposure of 
 
mg/m2 bid in participants with BSA ≥ 0.70 m2. The modelling accounts for possible differences in 
absorption and metabolism (CYP enzyme maturation processes) in children under 3 years old. For 
BSA 0.7 m2 and above, dosing recommendations with the granule formulation are in line with 
dosing recommendations for the selumetinib commercial capsule formulation. The final granule 
formulation dosing schema for selumetinib will be established during the dose-finding phase of the 
study (See Section 6.1.2)
Table 7
Initial Proposed Granule Formulation Dose Schema for Selumetinib
BSA (m2)
Granules Dose (bid approximately 
12 hours apart)
Dose level (mg/m2)
0.40 - 0.49
 mg
0.50 - 0.59
 mg
0.60 - 0.69
mg
0.70 - 0.89
 mg
0.90 - 1.09
 mg
1.10 - 1.29 a
 mg
a.
In the rare circumstance that a participant is unable to transition to capsule selumetinib when they attain a BSA 
between 1.10 and 1.29 m2 participants can continue to receive the granule formulation at the dose shown in 
Table 8.
Note that only one dose of selumetinib will be taken on C1D1; bid dosing will start on C1D2.
bid, twice daily; BSA, body surface area; C, cycle; D, day. 
At enrolment participants must have a BSA within the range 0.40 to 1.09 m2. Once participants 
attain a BSA between 1.10 and 1.29 m2 they will be encouraged to completely transition to the 
capsule formulation, if feasible, although all participants must remain on the granule formulation 
until after they have completed their third cycle of treatment. Upon transition to the capsule 
formulation, PK sampling should be performed on Day 7 (range Day 4 to 14) as long as the 
participant has received 3 consecutive days of twice daily dosing with capsule formulation 
immediately prior to the PK day, see Section 8.6.1.1 for more details. The dosing schedule for the 
capsule formulation is shown in Table 8.
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Table 8
Capsule Dose Schema for Selumetinib 25 mg/m2 bid
BSA (m2)
Capsule Dose (bid approximately 
12 hours apart)
Dose level (mg/m2)
1.10 - 1.29 m2
30 mg
23.3 - 27.3
1.30-1.49 m2
35 mg
23.5 - 26.9
1.50-1.69 m2
40 mg
23.7 - 26.7
1.70-1.89 m2
45 mg
23.8 - 26.5
≥ 1.90 m2
50 mg
20.0 - 26.5
bid, twice daily; BSA, body surface area.
Granules from the sprinkle capsule should be mixed with a dosing vehicle prior to administration. 
Detailed instructions will be provided in the IMP handling instruction document or an equivalent 
document.
The time and content of meals on intensive PK sampling days (Cycle 1 Day 1, Cycle 2 Day 1 and, 
should the participant transition to capsule formulation, capsule dosing Day 7) should be recorded 
in source data.
Selumetinib granules are administered twice a day, approximately 12 hours apart. For participants 
aged ≥ 1 to < 4 years selumetinib granules can be taken without regard to food.
For participants aged ≥ 4 to < 7 years, on intensive PK sampling days (Cycle 1, Day 1 and Cycle 2, 
Day 1), selumetinib granules must be taken on an empty stomach (no food or drink other than water 
for 2 hours before and one hour after dosing, with the exception of vehicle and water to cleanse the 
palate). On other study treatment days selumetinib may be taken without regard to food.
Where capsules are taken, selumetinib capsules should be swallowed whole with a glassful of water 
twice a day, approximately 12 hours apart, on an empty stomach (no food or drink other than water 
for 2 hours prior to dosing and one hour after dosing).
If a dose of selumetinib is missed, it should only be taken if it is more than 6 hours until the next 
scheduled dose. Do not take an additional dose if vomiting occurs after selumetinib administration 
but continue with the next scheduled dose.
6.1.2
Dose-finding Phase
The study includes an initial dose-finding phase designed to determine the dose schema for the 
granule formulation of selumetinib. Participants in the dose-finding phase at the recommended 
granule formulation dose schema will be analysed as part of the cohort for efficacy and safety at the 
primary analysis, the analysis after 25 cycles and the final analysis.
The physiologically-based PK model will be updated, if required, based on emerging PK data and 
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Only participants enrolled in the Global Cohorts will participate in the dose-finding phase of the 
study.
Dose-finding Process
Data from three evaluable participants in Cohort 1 (participants aged ≥ 4 to < 7 years of age) are 
needed for the dose-finding phase. After the completion of at least one cycle of dosing in the first 
3 evaluable participants, the SRC will evaluate the PK, safety, and tolerability of the granule 
formulation. To ensure that there are 3 evaluable participants in each dose finding phase, a 
maximum of 4 participants will be dosed. Should participants be classed as non-evaluable for the 
dose finding phase, additional participants will be dosed to ensure there is a minimum of 3 
evaluable participants (maximum 4 evaluable participants). Dosing of additional participants in the 
study will be paused whilst the SRC convenes to assess the PK and safety data at the end of the 
dose-finding phase in the first 3 evaluable participants.
If the SRC determines that the selumetinib AUC0-12 and safety are within the acceptable criteria 
(See Section 6.1.2.1) dosing of additional participants into Cohort 1 will continue, and dosing in the 
dose finding phase for Cohort 2 (participants aged ≥ 1 to < 4 years) will commence (as described 
below). 
If the SRC determines that the selumetinib AUC0-12 and safety are not within the acceptable 
criteria (See Section 6.1.2.1) dose adjustments will be made. Additional participants will be dosed 
into Cohort 1 in order to have an additional 3 evaluable participants. The dose-finding phase will 
continue to be assessed in this way until the granule formulation dose schema is identified and 
recommended for Cohort 1 (see Figure 2).
Once the selumetinib granule formulation dose schema is identified for Cohort 1, dosing in cohort 2 
will commence in order to have 3 evaluable participants in Cohort 2 in the dose-finding phase. After 
the completion of at least one cycle of dosing in the first 3 evaluable participants, the SRC will 
evaluate the PK, safety, and tolerability of the granule formulation at this dose schema. To ensure 
that there are 3 evaluable participants in each dose finding phase, a maximum of 4 participants will 
be dosed. Should participants be classed as non-evaluable for the dose finding phase, additional 
participants will be dosed to ensure there is a minimum of 3 evaluable participants (maximum 4 
evaluable participants). Dosing of additional participants in Cohort 2 will be paused whilst the SRC 
convenes to assess the PK and safety data in the first 3 evaluable participants.
If the SRC determines the granule formulation dose schema is within the acceptable criteria (See 
Section 6.1.2.1) dosing of additional participants in Cohort 2 will continue.
If the SRC determines the granule formulation dose schema is not within the acceptable criteria 
(See Section 6.1.2.1) and the dosing regimen will be amended, recruitment into Cohort 2 will 
continue in order to have an additional 3 evaluable participants in the dose-finding phase using the 
new dosing schema.   
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schema is identified and recommended for Cohort 2.
Following identification and recommendation of the granule formulation dose schema based on data 
from at least 3 evaluable participants, an additional SRC will be held for each of the cohorts 
following at least one cycle of dosing in approximately 6 evaluable participants. The SRC will 
evaluate the PK, safety and tolerability of the granule formulation at this dose schema.
If the SRC determines the granule formulation dose schema is within the acceptable criteria (See 
Section 6.1.2.1)  dosing to the cohort will continue. If the SRC determines the granule formulation 
dose schema is not within the acceptable criteria (See Section 6.1.2.1). The dosing regimen will be 
amended, dosing to the cohort will continue in order to have 3 evaluable participants using the new 
dosing schema. The dose-finding phase for the cohort will re-start and an SRC will be held after 3 
evaluable participants have completed at least one cycle of dosing and again after approximately 6 
participants have completed at least one cycle of dosing.  
An SRC will also be held for each of the cohorts following approximately one cycle of dosing in
approximately 10 evaluable participants, the minimum sample size required for the cohort at the 
recommended granule dose schema (See Section 9.2). The SRC will evaluate the PK, safety, and 
tolerability of the granule formulation at this dose schema. Sample size may be re-evaluated in each 
cohort based on the observed PK variability in approximately 
 evaluable participants and 
therefore could increase for the final statistical analysis of PK data (scenarios are outlined in 
Table 17). The final analysis will compare the exposure to selumetinib for this study with that for 
the capsule formulation (SPRINT 25 mg/m2).
In the situation where the dose schema is changed following evaluation of the PK, safety and 
tolerability, the SRC may decide to amend the dose schema for participants who started treatment in
the study on an alternative dose schema.
6.1.2.1
Pharmacokinetics and Safety/Tolerability Acceptability Criteria for the 
Dose-finding Phase
The primary comparison will be single dose individual and median AUC0-12 derived from 
participants in this study with the AUC0-12 
 percentile observed in the SPRINT study at 
 mg/m2. Single dose AUC0-12 is recommended as minimal accumulation was observed in adult 
and paediatric participants following chronic bid dosing and sample size estimations are based on 
variability in the granule formulation from single dose AUC. In addition, assessment with single 
dose AUC0-12 allows timely dose adjustments if required and it is more probable than with 
multiple doses to obtain the full 12 hour profile for the AUC0-12 estimation.
Acceptance Criteria for PK Parameters (n = 3)
∀
If 
 participants AUC data are outside of the SPRINT 
 percentile and the 
median is within the 
 percentile; then the dose schema will not be adjusted and the 
recruitment will continue at this dose schema.
∀
If 
 participants AUC are outside of the SPRINT 
 percentile then the dose 
schema may be adjusted proportionally, based on the geometric mean NCA AUC for 
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SPRINKLE to that observed in the SPRINT study. Dose schema may not be adjusted if the 
geometric mean AUC0-12 is within 
% of that of SPRINT. If the dose schema is adjusted, 
then the AUC will be re-assessed at the adjusted dose schema to confirm with an additional 3 
participants that exposure is within the 
 percentile of SPRINT exposure.
Acceptance Criteria for PK Parameters (n = 6)
∀
If 
 participants AUC data are outside of the SPRINT 
 percentile and 
the median is within the 
 percentile; then the dose schema will not be adjusted and 
the recruitment will continue at this dose schema.
∀
If 
 participants AUC are outside of the SPRINT 
 percentile then the dose 
schema may be adjusted proportionally, based on the geometric mean NCA AUC for 
SPRINKLE to that observed in the SPRINT study. Dose schema may not be adjusted if the 
geometric mean AUC0-12 is within 
% of that of SPRINT. If the dose schema is adjusted, 
then the AUC will be re-assessed at the adjusted dose schema to confirm with an additional  
participants that exposure is within the
 percentile of SPRINT exposure.
Safety Acceptance Criterion: 
∀
No unacceptable safety findings as determined by SRC.
6.1.2.2
Definition of an Evaluable Participant for the Dose-finding Phase
∀
For PK: has a PK profile on Day 1 without any important protocol deviations potentially 
impacting the PK results. 
∀
For Safety: if in the first cycle they receive at least 75% of study drug or experience a safety 
event. Has completed minimum safety evaluation requirements or experiences a safety event. 
6.2
Preparation/Handling/Storage/Accountability
AstraZeneca will supply selumetinib granule formulation  mg (white/white) and 
 mg 
(white/blue) sprinkle capsules in 
 count bottles and 
 mg (white) and 
 mg (blue) capsules in 
count bottles to the Investigator sites.
Selumetinib should be kept in a secure place according to the labelled storage conditions.
The Investigator or designee must confirm appropriate conditions have been maintained during 
transit for all selumetinib received and any discrepancies are reported and resolved before use of 
selumetinib.
Only participants enrolled in the study may receive selumetinib and only authorised site staff may 
supply or administer selumetinib. All selumetinib must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorised site staff.
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The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
Selumetinib may be delivered to a participant’s home by a designated courier, if required. 
Unused selumetinib should be returned to the site and disposed of according to local practice. 
6.3
Measures to Minimise Bias: Randomisation and Blinding
The study is open-label and single arm; there is no randomisation. 
At screening (Days -28 to -1) the Investigator or suitably trained delegate will:
1
Obtain signed informed consent from the legally authorised representative (parent or guardian) 
of the participant and assent from the participant (if deemed appropriate as per local 
regulations) before any study specific procedures are performed. Informed consent may be 
signed within 42 days of dosing window if it is more convenient for the site and families. If 
laboratory procedures were performed for alternate reasons prior to signing consent, these can 
be used for screening purposes with consent of the legally authorised representative (parent or 
guardian) of the participant. However, all screening laboratory and imaging results must have 
been obtained within 28 days of the first dose of study intervention.
2
Obtain a unique 7-digit enrolment number (E-code), through the IRT in the following format 
 
 This number is the participant’s unique identifier and 
is used to identify the participant on the eCRFs.
3
Determine participant eligibility (see Section 5.1 and Section 5.2 for inclusion and exclusion 
criteria, respectively).
On Day 1, once the participant is confirmed to be eligible, the Investigator, or suitably trained 
delegate, will:
1
Log in to IRT for treatment assignment or registration.
2
Participants may be enrolled but not treated. If the participant is not treated, the IRT should be 
accessed to terminate the participant in the system.
3
The IRT will be used to track drug supply.
4
Participants will begin treatment on Day 1. Participants must not be treated unless all eligibility 
criteria have been met.
If a participant withdraws from the study, then his/her enrolment code cannot be reused.
Investigators should keep a record (i.e., the participant screening log) of participants who entered 
screening.
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Procedures for Handling Incorrectly Enrolled Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study intervention. There can be no exceptions to this rule. Participants who are enrolled 
but subsequently found not to meet all the eligibility criteria must not be started on study 
intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is incorrectly started on treatment, 
the Investigator should inform the AstraZeneca Medical Monitor immediately, and a discussion 
should occur between the AstraZeneca Medical Monitor and the Investigator regarding whether to 
continue or discontinue the participant from treatment. The AstraZeneca Medical Monitor must 
ensure all decisions are appropriately documented and that the potential benefit/risk profile remains 
positive for the participant.
6.4
Study Intervention Compliance
When participants are dosed at the site (eg, PK days), they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date, and time if applicable, of 
dose administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.
Parents/guardians of the participant will complete a daily drug diary to record the dates and times 
on which selumetinib is taken.
When participants (self/parent/guardian) administer study intervention at home, compliance with 
study intervention will be assessed at each visit. Compliance will be assessed by counting returned 
sprinkle capsules or capsules and reviewing the Drug Diary at each site visit and documenting in the 
source documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded 
in the eCRF.
A record of the number of selumetinib sprinkle capsules or capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose reductions will 
also be recorded in the eCRF.
The Investigational Product Storage Manager is responsible for managing the study intervention 
from receipt by the study site until the destruction or return of all unused study intervention.
6.5
Concomitant Therapy
Any medication, procedure or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving from the time of screening or 
receives during the study including the 30 day safety follow-up phase following the last dose of 
study intervention must be recorded in the eCRF along with:

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
Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
If any concomitant therapy is administered due to new or unresolved AE, it should be recorded. 
Participants must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Unless considered to be clinically indicated, participants should avoid taking other additional 
non-study medications that may interfere with the study medication. 
Strong or moderate inducers of CYP3A4 are not allowed at any time during the study. 
Concomitant use of strong or moderate inhibitors of CYP3A4 and CYP2C19 should be avoided 
until after the PK assessment on Cycle 2, Day 1. During the remainder of the study (i.e., from Cycle 
2, Day 2 onwards), if concomitant use of selumetinib with strong or moderate CYP3A4 and
CYP2C19 inhibitors is not avoidable, then the selumetinib dose should be reduced as shown in 
Appendix I. The participant should be monitored closely for potential toxicities. The AstraZeneca 
Medical Monitor should be contacted to discuss whether these participants should be withdrawn or, 
if deemed to be deriving a clinical benefit, can continue in the study. 
In vitro selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on the PK 
of concomitantly administered substrates of OAT3 cannot be excluded and they should be given 
with caution.
Additional Prohibited Concomitant Medication when taking Capsules
Selumetinib capsules contain vitamin E in the form of D-α-tocopheryl polyethylene glycol 1000 
succinate, a water-soluble form of vitamin E which acts as a formulation excipient. The maximum 
daily dose of vitamin E that a study participant may receive from selumetinib is approximately 
261.6 mg/day. Therefore, participants should discontinue any supplemental vitamin E at least 7 days 
prior to transitioning to selumetinib capsules, and should not take any supplemental vitamin E while 
receiving selumetinib capsules. High doses of vitamin E have been reported to cause bleeding and 
interfere with blood coagulation processes. Note that this restriction does not apply to participants 
being treated with the selumetinib granule formulation as it does not contain D-α-tocopheryl 
polyethylene glycol 1000 succinate.
Selumetinib should be administered with caution in participants who are also receiving concomitant 
coumarin anticoagulant medications (eg, warfarin). These participants should have their INR 
monitored/anticoagulant assessments conducted more frequently and the dose of the anticoagulant 
should be adjusted accordingly. 
Prohibited medications are shown in Table 9.

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Table 9
Prohibited Medications
Prohibited medication/class of drug
Usage (including limits for duration permitted and special situations in 
which it is allowed)
Other IMP 
Not allowed for 4 weeks or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention.
Not allowed during the study.
MEK inhibitor
Not allowed for 4 weeks or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention.
Not allowed during the study (with the exception of selumetinib study 
intervention).
Other systemic NF1-PN target 
treatment
Not allowed for 4 weeks or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention.
Not allowed during the study.
Radiotherapy
Not allowed for 6 weeks prior to the start of intervention.
Radiotherapy (before or during the study) not allowed on target or 
non-target PNs.
Growth factors 
Not allowed within the 7 days prior to study entry (date of ICF signature).
Blood (red cells or other blood 
derived products) transfusion
Not allowed within the 28 days prior to study entry (date of ICF signature).
Multivitamins containing vitamin E
Must be stopped 7 days prior to initiation of selumetinib capsules.
Not allowed during the study while being treated with selumetinib capsules.
Permitted while being treated with selumetinib sprinkle capsules.
Herbal supplements or medications 
known to be strong or moderate 
inducers of CYP3A4, or strong or 
moderate inhibitors of CYP3A4 and 
CYP2C19 (Appendix I)
Must be safely discontinued at least 14 days or 5 half-lives (whichever is 
longer) before the first dose of study medication.
Strong or moderate inducers of CYP3A4 are not allowed at any time during 
the study. 
Concomitant use of strong or moderate inhibitors of CYP3A4 and CYP2C19 
should be avoided until after the PK assessment on Cycle 2, Day 1. 
During the remainder of the study (i.e., from Cycle 2, Day 2 onwards), if 
concomitant use of strong or moderate CYP3A4 and CYP2C19 inhibitors is 
not avoidable, then the selumetinib dose should be reduced as shown in 
Appendix I.
CYP, cytochrome P450; ICF, informed consent form; IMP, investigational medicinal product; MEK, mitogen activated 
protein kinase; NF1, neurofibromatosis type 1; PK, pharmacokinetics; PN, plexiform neurofibroma.

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6.6
Dose Modification
Specific guidance for the management of AEs, including interruption or reduction of treatment with 
selumetinib, may be considered for particular events of special interest (eg, diarrhoea, dyspnoea, 
rash, asymptomatic reduction in LVEF, and visual disturbance), as indicated in the algorithms 
provided in Appendix E.
For all AEs reported in this study that are considered at least partly related to administration of 
selumetinib, the following dose reduction/adjustment guidance should be applied unless otherwise 
specified in the guidance for management of specific AE (Appendix E).
Treatment with selumetinib should be temporarily interrupted if one of the following AEs occurs 
and is considered related to treatment with selumetinib:

Any intolerable AE regardless of grade.

Any AE CTCAE Grade ≥3.
On improvement of the AE to CTCAE Grade 1 or less within 4 weeks of onset, study intervention 
may be restarted at the discretion of the Investigator. If restarted, it must be at a reduced dose as 
shown in Table 10 and Table 11. If the AE does not resolve to CTCAE Grade 1 or less within 4 
weeks of onset, study intervention must be permanently terminated unless otherwise specified in the 
Guidance for Management of Specific AEs (Appendix E). 
The dose modification procedure is shown in Table 10 and Table 11. Two step dose modification is 
applied in the study. Any participants with 2 prior dose reductions who experience a toxicity that 
would cause a third dose reduction must be discontinued from study intervention.
Dose must not be re-escalated following dose reduction apart from to account for increase due to 
BSA, in accordance with Table 10 and Table 11. For example, if a participant has a BSA of 1.2 m2
and starts on a capsule dose of 30 mg bid and then has a dose reduction to 25 mg AM, 20 mg PM 
then a subsequent BSA increase to 1.4 m2 would mean the participant should be dose adjusted to 25 
mg bid.
Note that if selumetinib treatment is interrupted for > 4 weeks for any reason other than AEs related 
to selumetinib eg, investigations, unplanned procedures and AEs unrelated to selumetinib, re-start 
of treatment must be discussed with the Medical Monitor.
Treatment with selumetinib should be permanently discontinued for any CTCAE Grade 4 toxicity 
that is at least partially related to selumetinib. However, if it is felt to be in the best interest of the 
participant, interruption of selumetinib with potential to restart at a reduced dose upon resolution to 
Grade 1 or less may be considered on a case-by-case basis for CTCAE Grade 4 AEs in consultation 
with the Medical Monitor.
As the initial proposed dose schema for the selumetinib granule formulation may be adjusted based 
on emerging safety, tolerability, and PK data, the dose reductions shown in Table 10 may not 

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include all scenarios. The principles for the granule formulation dose reduction are as follows:
∀
The reduced dose should be 25% lower than the non-tolerated dose.
∀
The reduced dose should be rounded down to the nearest achievable dose using the same 
granule formulation strengths, to minimise dosing errors.
Table 10
Granule Formulation Dose Modification Procedure based on Initial 
Proposed Granule Dose Schema
Body surface area (m2)
Selumetinib dose (mg) 
bid a starting dose
First selumetinib
dose (mg) bid reduction
Second selumetinib
dose (mg) bid reduction
0.40 – 0.49
0.50 – 0.59
0.60 – 0.69
0.70 – 0.89
0.90 – 1.09
1.10 – 1.29 b
a.
Actual dose in mg administered every 12 hours to achieve exposure approximately equivalent to capsule in 
SPRINT; target median AUC =
 ng/mL at selumetinib dose 
 mg/m2 BSA.
b.
In the rare circumstance that a participant is unable to transition to capsule selumetinib when they attain a BSA 
between 1.10 and 1.29 m2 participants can continue to receive the granule formulation at the dose shown in 
Table 8, and dose modifications should be as per Table 11.
AUC, area under the concentration-time curve; bid, twice daily; BSA, body surface area.
Table 11
Capsule Dose Modification Procedure
Body surface area (m2)
Selumetinib starting dose 
(mg) a
First selumetinib 
dose (mg) reduction
Second selumetinib 
dose (mg) reduction
AM
PM
AM
PM
AM
PM
1.1 to 1.29
30
30
25
20
20
10
1.3 to 1.49
35
35
25
25
25
10
1.5 to 1.69
40
40
30
30
25
20
1.7 to 1.89
45
45
35
30
25
20
≥ 1.9
50
50
35
35
25
25
a.
Actual dose in mg (capsule sizes 10 and 25 mg) administered every 12 hours to achieve a dosage of 25 mg/m2 bid.
bid, twice daily.
6.7
Continued Access to Study Intervention after the End of the Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
After the participant’s last visit, AstraZeneca will continue to supply selumetinib to participants 
whilst they are still receiving clinical benefit or until meeting any other discontinuation criteria as 
defined in Section 7.1. 
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AstraZeneca will continue to supply selumetinib in the continued access phase of this study while, 
in the opinion of the Investigator, the participant is benefiting. 
In the event that product development reaches a point where alternative product supply options 
become available, then these alternative product supply options will be discussed by AstraZeneca 
with the Investigator. AstraZeneca will work with the Investigator to transition the participant(s) to 
alternative supply, where possible.
In the event that a roll-over or safety extension study is available at the time of the final DCO and 
database closure, participant(s) currently receiving treatment with selumetinib may then be 
transitioned to such a study, and the current study may reach its end. The roll-over or extension 
study would ensure treatment continuation with visit assessments per its protocol, as applicable. 
Any participant who would be eligible to move to such a study would be given a new informed 
consent, as applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
In the following section the term “participant” also refers to the participant’s legally authorised 
representative acting on their behalf. 
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue selumetinib. See the SoA (Table 2
and Table 3) for data to be collected at the time of discontinuation of study intervention and follow-
up and for any further evaluations that need to be completed.
The Investigator should instruct the participant to contact the site before or at the time if study 
intervention is stopped. A participant that decides to discontinue study intervention will always be 
asked about the reason(s) and the presence of any AEs. The reason for discontinuation should be
documented in the source document and the appropriate section of the eCRF.
Participants who have permanently discontinued from further receipt of study intervention will need 
to be discontinued from the IRT. All study intervention should be returned by the participant at their 
next on-site study visit or unscheduled visit.
Participants may be discontinued from study intervention in the following situations: 

Disease progression based on the Investigator’s decision.

Investigator determination that the participant is no longer benefiting from study intervention.

An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further dosing.

Any AE that meets criteria for discontinuation defined in the dose modification guidelines for 
management of study intervention-related toxicities (see Section 6.6).

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment may continue to 

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participate in the study (eg, for safety) unless they specifically withdraw their consent to all 
further participation in any study procedures and assessments (see Section 7.2).

Severe non-compliance with the CSP as judged by the Investigator or AstraZeneca.

Pregnancy.

Initiation of systemic therapy for NF1-PN, including another investigational agent. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from the 
study.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, compliance, 
or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options to ensure the collection of endpoints and safety information 
including new AEs and follow-up on any ongoing AEs and concomitant medications (eg, 
telephone contact at 30 days (+ 7 days) after study intervention is discontinued, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, an End of Treatment visit should be 
conducted as shown in the SoA (Table 2). See SoA for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed.

The participant will discontinue selumetinib and be withdrawn from the study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulation. The Investigator 
must document the decision on use of existing samples in the site study records and inform the 
Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
Participants who decline to continue participation in the study, including telephone contact, should 
be documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators should 
document attempts to re-establish contact with missing participants throughout the study period. If 
contact with a missing participant is re-established, the participant should not be considered lost to 
follow-up and evaluations should resume according to the CSP.

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The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel them on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to be lost to 
follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA. Protocol waivers or exemptions 
are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count)
obtained before signing of the ICF may be utilised for screening or baseline purposes with 
consent of the legally authorised representative (parent or guardian) of the participant provided 
the procedures met the CSP-specified criteria and were performed within the time frame 
defined in the SoA.
8.1
Administrative and General/Baseline Procedures
N/A
8.2
Efficacy Assessments
8.2.1
Imaging of the Target PN
In 2013, consensus recommendations for the imaging of PN were issued by an international 
working group (REiNS) who recommended MRI volumetric PN assessment as preferable to all 
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recommended to sensitively and reproducibly evaluate changes in PN size in clinical studies. 
Volumetric analysis requires adherence to specific imaging recommendations and a 20% volume 
change was chosen to indicate a decrease or increase in PN size (Dombi et al 2013).
Extent of PN in patients with NF1 can be very substantial, and may not allow for all PNs to be 
followed using volumetric MRI. Both target and non-target PNs must be symptomatic, measurable 
and inoperable. Prior to starting treatment on this study, the investigator must select the target PN. 
The target PN is defined as the clinically most relevant PN (signs/symptoms/complications which 
have the most impact on the patient in the opinion of the Investigator), which is measurable by 
volumetric MRI analysis. If there is a second PN that is also considered clinically relevant, the 
investigator may select this as a non-target PN; only one non-target PN can be selected. 
AstraZeneca’s appointed imaging CRO will measure the target PN and non-target PN (if 
applicable). The management of participants will be based upon the results of the PN assessments 
conducted by the Investigator using their standard of care methods.
The MRI images, including unscheduled visit scans, will be collected on an ongoing basis and sent 
to an AstraZeneca-appointed imaging CRO for quality control, storage, and for ICR. The details 
about target PN location (most clinically relevant PN) and non-target PN location (if relevant) will 
also be collected to provide to the independent reviewer. Digital copies of all original scans should 
be stored at the Investigator site as source documents. An ICR of images will be performed for the 
assessment of efficacy according to the REiNS criteria as stated in the exploratory endpoints.
Results of these independent reviews will not be communicated to Investigators, and results of 
Investigator PN assessments will not be shared with the central reviewers. 
Screening imaging evaluation:

Identify and select the inoperable target PN (plus a maximum of one additional non-target PN). 
Should there be more than 2 inoperable PNs that meet the criteria for selection, the 2 most 
clinically relevant PNs will be followed by volumetric MRI analysis.

Perform volumetric MRI evaluation on the selected index PNs as outlined in the MRI 
acquisition guidelines.
On study imaging evaluation:
Unless clinically indicated otherwise, and as defined in Table 2, volumetric MRI of the target and 
non-target PNs should be performed at every 4 cycles (16 ± 1 weeks) relative to the date of first 
dose for the first 13 cycles, and subsequently every 6 cycles (24 ± 1 weeks). The MRI data for 
participants who discontinue selumetinib prior to Cycle 25 will be collected if a suitable MRI is 
performed as standard of care until the time when they would have completed 25 cycles of 
treatment, or they commence an alternative systemic NF1-PN treatment, whichever is the earliest. 
The REiNS assessment criteria of volumetric MRI of the target PN performed by the central 
imaging vendor are as follows:  

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∀
Complete response: disappearance of the target PN. The CR is considered unconfirmed at first 
detection and confirmed when observed again at a consecutive scan within 3 to 6 months.
∀
Partial Response: decrease in the volume of the target PN by 20% or more compared to 
baseline. The partial response is considered unconfirmed at the first detection and confirmed 
when observed again at a consecutive scan within 3 to 6 months.
∀
Stable disease: insufficient volume change to qualify for either partial response or PD.
∀
Progressive Disease: increase in the volume of the target PN by 20% or more compared to 
baseline or the time of best response after documenting a PR. The appearance of new PN (with 
the exception of new discrete subcutaneous neurofibromas as noted below) which is 
unequivocally and completely distinct and separate from the target PN and the non-target PN, 
or unequivocal progression of an existing non-target PN is also considered PD. In this study 
unequivocal progression is defined as an increase in the volume of the non-target PN by 20% or 
more compared to baseline.
The clinical appearance of new discrete subcutaneous neurofibromas does not qualify for disease 
progression. 
Participants who have completed any protocol-derived therapy (as little as one dose) will be 
considered evaluable for response.
8.2.2
Objective Response Rate
Objective response rate is defined as the percentage of participants with measurable disease who 
have a confirmed CR (defined as disappearance of the target PN, confirmed by a consecutive scan 
within 3 to 6 months after the first response) or confirmed partial response (defined as a target PN 
volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3 to 6 
months after the first response) as determined by ICR per REiNS criteria.
8.2.3
 is defined as the time from 
 until the 
 (by ICR per REiNS criteria) of 
 
 Progressive disease is an increase in target PN volume by 20% or more 
compared to baseline or compared to the time of best response after documenting a PR. The 
appearance of new PN (with the exception of new discrete subcutaneous neurofibromas) or 
unequivocal progression of existing clinically relevant non-target PN is also considered PD.
8.2.4
 is defined as the time from the date of 
 
 until date of 
 
 as determined by ICR per REiNS criteria).
8.2.5
 is defined as the time from 
 until the
 
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8.2.6
 is defined as the time from 
 until the 
 
 The first 
 should 
coincide with that used for the 
8.2.7
Clinical Outcome Assessments
A COA is any assessment that may be influenced by human choices, judgment, or motivation and 
may support either direct or indirect evidence of treatment benefit. A COA can be reported by a 
participant (patient-reported outcomes), a clinician, an observer, or through a performance-based 
assessment (FDA-NIH BEST Resource). A COA may be used in clinical studies to provide either 
direct or indirect evidence of treatment benefit. It is important to examine the impact of therapy on 
symptoms, function, and other 
of the participant to aid understanding of the risk-benefit 
profile. The following COA instruments will be administered in this study:
∀
∀
∀
∀
∀
∀
 
Where possible each COA assessment should be completed by the 
 
8.2.7.1
The 
 is an 
measurement used to assess 
 
, or for older individuals that are 
 It incorporates 
 
Each behaviour is scored between 
 
for this study the 
 for several 
minutes and then determines the score for each category. It has been validated in 
The same group later updated the
 
however, it has not been 
validated in an NF1 patient population specifically. This will be completed daily in the evening for 
7 days after the visits specified in the SoA. The
 will be completed by the 
 
 at time of study entry (date of signature of consent) or those who in 
the opinion of the Investigator are 
.
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A copy of the scale is provided in Appendix J 1.
The 
 is a 
 measure of
 
 are presented to the child, who will 
then 
 giving a score. The scale 
shows a close linear relationship with 
 across the age range of
 
 In this study, the 
will be used to assess 
 in 
children aged
 years of age at time of study entry (date of signature of consent) 
 
 daily in the evening according to the schedule specified in the SoA (Table 2).
A copy of the scale is provided in Appendix J 2.
8.2.7.2
The 
is a 
measure used to assess 
 
 This will provide complementary information to the 
 
 to inform change over time in 
 while minimising recall bias.
A copy of the scale is provided in Appendix J 3.
8.2.7.3
The 
 is a 
 measure used to
 
. It uses as a
 and will 
be used as a supportive assessment to the 
and 
 to ensure a common assessment 
across age range.
A copy of the scale is provided in Appendix J 4.
8.2.7.4
The 
 is a widely accepted measure for 
 
The 
 are multidimensional 
 
. The 
 is a brief standardised 
 scale with 
good reliability and validity, which includes both 
 It consists 
of a 
 
The 
 have been developed in 
. In this study, 
 will be used.
 
 will be used in this study. The questionnaire takes 
approximately
 minutes to complete and will be used for participants aged
 years as 
shown in Table 12.
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The 
 consists of
 
. It is a 
 and the 
 version will be used in this study for participants 
 years as shown in 
Table 12.
Table 12
A copy of the scale is provided in Appendix J 5.
8.2.7.5
A 
will be used to ensure that
 
 Information on 
 
will be collected, including 
 The 
survey will be completed by 
 on paper in the evening for 7 days prior to the 
visits specified in the SoA and verified by the Investigator or delegate.
8.2.7.6
Palatability
An assessment of palatability (the overall appreciation of the product in relation to its smell, taste, 
aftertaste and texture) will be conducted using a parent-reported observer palatability assessment. It 
is a 3-item measure with dichotomous responses, assessing willingness to swallow and other 
observed behaviour on administration of an oral medication.  
A copy of the palatability scale is provided in Appendix J 6.
8.2.7.7
Administration of Electronic Questionnaires 
Questionnaires will be completed by the participant’s parent or guardian (or, where relevant, the 
participant) using electronic devices at the time points indicated in the SoA. The questionnaires may 
be completed at study sites if the assessment time point coincides with a scheduled site visit; 
otherwise, the questionnaires should be completed at home. 
Each site must allocate the responsibility for the administration of the instruments to a specific 
individual (eg, a research nurse or study co-ordinator) and, if possible, assign a backup person to 
cover if that individual is absent.
Approximately 10 to 20 minutes is required for participants to complete the questionnaires.
The below instructions should be followed when collecting questionnaire data via an electronic 
device:
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
At the site, the questionnaires should be completed prior to any other study procedures or 
discussions (following informed consent), including medication treatments, and before 
discussion of disease progression that could bias the responses to the questions.

The questionnaires should be completed in a quiet and private location.

The parent/guardian or participant should be given sufficient time to complete the 
questionnaires at his/her own speed.

The research nurse or appointed site staff should explain to the parent/guardian or participant 
the value and relevance of these data so they are motivated to comply with questionnaire 
completion.

The research nurse or appointed site staff should stress that the information is not routinely 
shared with study staff. Therefore, if the participant has any medical problems, the 
parent/guardian or participant should discuss them with the doctor or research nurse separately 
from the assessment.

The research nurse or appointed site staff must train the parent/guardian or participant on how 
to use the electronic device using the materials and training provided by the ePRO vendor.

The research nurse or appointed site staff must provide guidance on whom to call if there are 
problems with the device when the parent/guardian or participant is completing the 
questionnaires at home.

All questionnaires must be completed using the electronic device; paper questionnaires are not 
allowed in this study. 

The research nurse or appointed site staff must remind participants that there are no right or 
wrong answers and avoid introducing bias by not clarifying items.
Completion of Questionnaires at Clinic Visits:

If a parent/guardian or participant uses visual aids (eg, spectacles or contact lenses) for reading 
and does not have them when he or she attends the clinic, the participant will be exempted from 
completing the questionnaires at that clinic visit.

Site staff must not complete the ePRO questionnaires on behalf of the participant. 

Site staff must provide questionnaires available in the language that the participant speaks and 
understands. Questions must not be read in an available language and translated into another 
language for the participant.

It is critical that the questionnaires are completed as specified in the SoA to capture the effect 
of study intervention.
Completion of Questionnaires at Home:

Reminders should be sent to parent/guardian or participants at home as needed to ensure 
compliance with the assessment schedules.

The same parent/caregiver should complete the questionnaires at home or at the site.  

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∀
Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits, and document the reason(s) why a parent/guardian or 
participant could not complete assessments, in the source documents and in the designated 
eCRF. If compliance drops to or below 85%, they will be flagged in the routine compliance 
report generated by the ePRO system, and appropriate action will be taken (eg, discussion with 
parent/guardian or participant to improve compliance, a check in call from the site to ask the 
parent/guardian or participant if they have any difficulties in completing questionnaires on 
schedule, etc).
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 2 and Table 3).
8.3.1
Physical Examination Including 
A complete physical examination will be performed and include assessments of the following; 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, 
nose, and throat), lymph nodes, thyroid, muscular-skeletal (including spine and extremities), 
urogenital, dermatological, gastrointestinal, endocrine, hematologic/lymphatic and 
 
 Targeted physical examinations are to be used by the Investigator on the basis of clinical 
observations and symptomatology.
An abbreviated physical examination will include, at a minimum, assessments of the general 
appearance, respiratory and cardiovascular systems, skin and abdomen (liver and spleen) as 
clinically indicated.
Physical examination will be performed at time points as specified in the SoA; Investigators should 
pay special attention to clinical signs related to previous serious illnesses, new or worsening 
abnormalities may qualify as AEs, see Section 8.4.5 for details.
If unexplained muscle weakness or myalgia (muscle pain) occurs, the participant should have a 
neuromuscular examination, urine analysis and CK measurement performed (with an additional 
CK-MM isoform measurement where possible) and be managed according to local practice.
8.3.2
Height and Weight
Height and weight will be measured at the times outlined in the SoA. The participant’s height will 
be recorded in cm and weight will be recorded in kg. Height and weight measurements will be 
performed in light clothing and with shoes off. Children under 2 years of age and those who are 
unable to stand stably enough to be measured in the standing position should be measured in the 
supine position on a measuring board (eg, Kiddimeter). 
Collect all available documented previous height and weight measurements and growth curves if 
available at screening.
Height: The participants should take off shoes and socks, and heels should be placed against a wall 
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with ankles together. Height should be measured in a standing position with a stadiometer. Height 
measurements should be taken at approximately the same time of day for each visit, when possible. 
The height should be plotted on a standardised growth chart. In participants with known leg length 
discrepancy due to limb hypertrophy, height should be measured with the participant bearing weight 
on the limb without hypertrophy.
Body Surface Area should be calculated using the formula derived by Mosteller: 

√ (weight (kg) x height (cm) / 3600
8.3.3
Vital Signs
Vital signs will be performed at timelines as specified in the SoA.
Temperature, pulse rate, oxygen saturation by pulse oximetry, respiratory rate, and BP will be 
assessed. 
Blood pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).
Three consecutive BP readings will be recorded at intervals of at least one minute. The average of 
the 3 BP readings will be recorded on the eCRF. 
8.3.4
Electrocardiograms
An ECG will be performed at time points as specified in the SoA.
Single 12-lead ECGs will be obtained locally at the site. Electrocardiograms will be evaluated at the 
times outlined in Table 2 and Table 3 using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTcF intervals. Participants that were enrolled on CSP 
Version 1.0 (therefore with QTcB as an exclusion criterion at screening), should have both QTcB 
and QTcF collected at all timepoints throughout the study, and QTcF should be retrospectively 
calculated and reported for all visits that have previously occurred. Participants should be supine 
(where possible) and at rest 5 minutes prior to recording the ECG.  
The Investigator should review the paper copy of the ECGs on each study day and may refer to a 
local cardiologist if appropriate.
If an abnormal ECG finding at the screening assessment is considered to be clinically significant by 
the Investigator, it should be reported as a concurrent condition. During the study, clinically 
significant abnormal ECG findings not present at screening should be reported as an AE. If present, 
the clinical signs and symptoms associated with the abnormal finding should be reported as an AE, 
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Single ECGs should be performed at the time of significant LVEF drop (Section 8.3.5) and on 
occurrence of any cardiorespiratory AEs with no obvious diagnosis. For participants with new or 
worsening respiratory symptoms (such as dyspnoea or cough), an ECG is recommended, and 
additionally at the discretion of the Investigator if clinically indicated.
8.3.5
Echocardiogram
An ECHO to assess LVEF will be performed at the visits as shown in the SoA. Participants should 
be examined using the same machine and operator whenever possible, and quantitative 
measurements should be taken (i.e., accurate to 1% and not estimated to 5%).
Left ventricular ejection fraction, end diastolic, and end systolic left ventricular volumes should be 
recorded at each ECHO assessment. 
Participants experiencing an asymptomatic LVEF reduction or left ventricular systolic dysfunction 
should be managed according to the algorithm provided in Appendix E 1. 
Participants who have a drop in LVEF of ≥ 10 percentage points from baseline and to below the 
LLN at the time of selumetinib discontinuation should, where possible, have follow-up ECHO, 
ECG, vital signs and weight performed after 30 days to evaluate the potential for reversibility.
An ECHO will also be carried out if a participant develops signs and/or symptoms suggestive of 
deterioration in left ventricular function/cardiac event. 
A further ECHO should be performed as part of the assessment package for any cardiorespiratory 
AE with no obvious diagnosis (obvious causes will be managed in accordance with local clinical 
practice) and additionally at the discretion of the Investigator if clinically indicated.
If a participant has had an ECHO performed within 4 weeks prior to treatment discontinuation, the 
discontinuation visit ECHO scan is not required unless clinically indicated.
Concomitant cardiac symptoms should be reported as AEs/SAEs accordingly. Cardiac failure 
should be treated and followed according to local medical practice.
8.3.6
Ophthalmologic Examinations
An ophthalmologic examination (age appropriate best corrected visual acuity, IOP and slit-lamp or 
indirect fundoscopy) will be evaluated at the times outlined in the SoA, and as clinically indicated 
whilst the participant is on study intervention. The participant should be examined using the same 
machine and operator throughout the study wherever possible.
If a participant experiences symptoms of visual disturbance (including blurring of vision), a 
complete ophthalmological examination, including a slit-lamp or indirect fundoscopy examination, 
must be performed. If an abnormality is detected, fundus photography and an optical coherence 
tomography scan can also be performed where required. Adverse events are to be managed 
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If a retinal abnormality prior to or at the time of selumetinib discontinuation is observed, a repeat 
ophthalmological examination is to be performed 30 days after discontinuation of selumetinib in 
order to document reversibility. Abnormalities should be followed up. 
8.3.7
Knee/Wrist MRI/X-ray
Yearly growth assessments require integration of information including height measurements and 
bone age if clinically indicated, which should be plotted onto growth charts. Children with impaired 
growth velocity should be referred to a paediatric endocrinologist as clinically indicated for 
evaluation, and should be followed until they reach final adult height. 
An MRI/X-ray of the knee will be performed at screening as specified in Table 2 and Table 3, and if 
clinically indicated, to monitor growth plates for any signs of physeal dysplasia. The imaging 
modality that is used at baseline (MRI/X-ray) must be used at all follow-up visits throughout the 
study. A wrist MRI/X-ray is acceptable if it is not possible to perform knee MRI/X-ray. The joint 
imaged (left/right, wrist/knee) must be consistent throughout the study, except occasions where 
MRI/X-ray of the joint imaged at baseline is not possible. Where feasible the knee/wrist MRI/X-ray 
will be performed at the same time as the PN volumetric MRI.
The investigator should regularly look for signs of physeal dysplasia (eg, joint pain and fatigue after 
exercising, abnormal gait, and spine irregularities). Children who show signs of physeal dysplasia at 
the time of selumetinib discontinuation should have a follow-up assessment after 30 days to 
evaluate the potential for reversibility.
8.3.8
Performance Status
Performance status will be measured as indicated in the SoA; the Lansky performance scale is 
described in more detail in Appendix G.
Any significant change from baseline or screening must be reported as an AE.
8.3.9
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis will be 
taken at the visits indicated in the SoA.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units and reference ranges) will be 
recorded on the appropriate eCRF. 
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at or near 
to the investigator site. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at the site.
The laboratory variables shown in Table 13 will be measured.

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Table 13
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical chemistry (serum or plasma)
B – Haemoglobin
S/P – Albumin
B – Platelet count
S/P – Alkaline phosphatase
B – Leukocyte count
S/P – Alanine aminotransferase 
B – Leukocyte differential count (absolute count)
S/P – Aspartate aminotransferase
B – Absolute Neutrophil count
S/P – Total calcium
B – Absolute Lymphocyte count
S/P – Creatinine a
B – Total white blood cell count
S/P – Gamma-glutamyl transferase
B – Total red blood cell count
S/P – Magnesium
S/P – Phosphate
S/P – Potassium
S/P – Sodium
Urinalysis (dipstick) b
S/P – Total protein
U – Glucose
S/P – Total bilirubin
U – Protein/albumin 
S/P – Urea nitrogen c
U – Haemoglobin/erythrocytes/blood
S/P – Creatine kinase d
S/P – Amylase
S/P – Troponin (isoform per site norm) e
a.
Creatinine clearance and glomerular filtration rate to be calculated at screening and if clinically indicated. 
b.
Urine microscopy will be assessed if other urinalysis measurements are abnormal or if clinically indicated
c.
Urea or blood urea nitrogen based on local site practice.
d.
Creatine Kinase to be assessed in accordance with the schedule of assessments and if unexplained muscle 
weakness or myalgia (muscle pain) occurs. See Section 8.3.1 for additional information.
e.
Troponin (isoform per site norm), should be assessed at screening, and performed when there is a significant drop 
in LVEF (of ≥10 percentage points relative to baseline and to an absolute LVEF below the institution’s LLN on 
study intervention) or for any cardiorespiratory events with no obvious diagnosis. If troponin assessments are not 
available, per local practice, CK-MB isoform should be assessed. Participants should be managed according to the 
algorithm provided in Appendix E 2.
B, blood; CK-MB, creatine kinase-myocardial band; LLN, lower limit of detection; LVEF, left ventricular ejection 
fraction; P, plasma; S, serum; U, urine.
In case a participant shows an AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN 
please refer to Appendix D, Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law, for further instructions. 
The Investigator should assess the available results with regard to clinically relevant abnormalities. 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated and 
recorded on the eCRF. Situations in which laboratory safety results should be reported as AEs are 
described in Section 8.4.5.

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All participants with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study intervention must be followed and have further tests performed until the laboratory 
values have returned to Grade 1 or 2, unless these values are not likely to improve because of the 
underlying disease.
8.3.10
Other Safety Assessments
8.3.10.1
Appropriate 
 will be used based on age of the participant at the time of the 
assessment:
The 
 is one of the most reliable and widely used tests for 
 
. The 
 is derived from the 
 
 
. It can be administered in 
 minutes
 The 
of 
participants aged 
 years will be evaluated with this test. 
The 
consists of 
 
 
 The 
 consist of 
In the context of this study 
 
 Both
 include
. The 
 
 are used to compute the 
 score and 
 scores: 
 
 The 
 measure aspects of 
 The 
 
 takes approximately 
minutes to complete
 The 
 of participants aged 
years will be evaluated with this test.  
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The 
, currently in its 
edition, is a widely used and 
accepted test of 
. In the context of this study, only the
 is required, 
there is no need to perform 
 
The 
is validated for administration to people aged 
years (there is no upper limit) and 
takes 
minutes to complete. The 
of participants aged
 years will be 
evaluated with this test 
 
8.4
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from the time of signature of the ICF until 30 days after the last 
dose of selumetinib or 25 cycles of treatment, whichever is earlier. For participants taking part in 
the long term safety follow-up (participants < 5 years of age), after 25 cycles of treatment or end of 
treatment, adverse events causally related to selumetinib will be collected until they complete the 
study in accordance with Table 3. No AEs will be collected for participants who are > 5 years of age 
who remain in the study after 25 cycles of treatment.
SAEs will be collected from time of signing the ICF throughout a subject’s participation in the 
study.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the IMP that 
occurs after the end of the clinical study in a participant treated by him or her, the Investigator shall, 
without undue delay, report the SAE to the Sponsor.
8.4.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
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Adverse Event Variables
The following variables will be collected for each AE:

The AE (verbatim)

The date and time when the AE started and stopped

The CTCAE grade/max CTCAE grade/changes in CTCAE grade

Whether the AE is serious or not (Appendix B)

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to Investigational Product

If the AE caused participant’s withdrawal from study (yes or no)

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

Adverse event 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
The grading scales found in the revised NCI CTCAE Version 5.0 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 can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov). 
8.4.3 Causality Collection
The Investigator should assess causal relationship between Investigational Product 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 Investigational Product?’
For SAEs causal relationship should 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 

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implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP. 
8.4.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider or reported in response to the 
open question from the study site staff: ‘Has 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 eCRF. 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.
8.4.5 Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests, vital signs, physical examinations, ECGs, 
ECHO scans and ophthalmological examinations will be summarised in the Clinical Study Report. 
Deterioration as compared to baseline in CSP-mandated laboratory tests, vital signs, ECGs, 
echocardiogram scans and ophthalmological examinations should therefore only be reported as AEs 
if they fulfil any of the SAE criteria, are the reason for discontinuation of treatment with the 
investigational product or are considered to be clinically relevant as judged by the Investigator 
(which may include but not limited to consideration as to whether treatment or non-planned visits 
were required or other action was taken with the study intervention, eg, dose adjustment or drug 
interruption).
If deterioration in a laboratory value/vital sign/ECG/ECHO is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result/vital 
sign/ECG/ECHO 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 
non-mandated 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 unless unequivocally related to 
the disease under study.
8.4.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may need to be reported as 
SAEs. Please refer to Appendix D for further instruction on cases of increases in liver biochemistry 
and evaluation of HL.

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8.4.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable to the 
disease for which the study intervention 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. The development of new 
symptoms, or the progression of existing symptoms, of NF1-PN should be considered as disease 
progression and not an AE. Events which are unequivocally due to disease progression should not 
be reported as an AE during the study.
8.4.8 Disease under Study
Symptoms of disease under study are those which might be expected to occur as a direct result of 
NF1-PN. Events which are unequivocally due to disease under study should not be reported as an 
AE during the study unless they meet SAE criteria or lead to discontinuation of the study 
intervention.
8.4.9
Reporting of Serious Adverse Events
All SAEs must be reported, whether or not considered causally related to the study intervention, or 
to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, Investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one 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 will be undertaken immediately. Investigators or other site personnel will inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one calendar day, 
i.e., immediately but no later than 24 hours of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone followed by completion of a paper SAE 
form.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the Investigator’s Brochure for 

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selumetinib. 
In the European Union, the Sponsor will comply with safety reporting requirements and procedures 
as de-scribed in the European Clinical Trials Regulation (EU) No 536/2014. All Suspected 
Unexpected Serious Adverse Reactions (SUSARs) to investigational medicinal product will be 
reported to the EudraVigilance database within the required regulatory timelines.
8.4.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study intervention.
8.4.10.1
Maternal Exposure
Not applicable due to age of participants. 
8.4.10.2
Paternal Exposure 
Not applicable due to age of participants.
8.4.11
Medication Error, Drug Abuse, and Drug Misuse
8.4.11.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within one 
calendar day, i.e., immediately but no later than 24 hours of when they become aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within one (Initial Fatal/Life-Threatening or follow-up Fatal/Life-
Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE associated 
with the medication error, drug abuse, or drug misuse (see Section 8.4.9) and within 30 days for all 
other events. 
8.4.11.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an IMP/study intervention or AstraZeneca NIMP that either causes harm to 
the participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix B 4.
8.4.11.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP/study 
intervention or AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.

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8.4.11.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorised product 
information, or for unauthorised IMPs/study intervention(s) or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol and includes deliberate administration of the product by the 
wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
8.4.12
Medical Device Deficiencies
This section is not applicable for this study. 
8.4.13
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the further 
understanding of the selumetinib safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI can be serious or non-serious. All 
AESI should be recorded in the eCRF as soon as possible, and preferably within 24 hours of 
occurrence. Serious AESIs will be recorded and reported as per Section 8.4.9. Adverse events of 
special interest based on examinations and tests should be reported in accordance with Section 
8.4.5.
Adverse events of special interest are shown in Table 14.
Table 14
Adverse Events of Special Interest
AESI
MedDRA Preferred Terms Defining the AESIs
Ocular toxicity
Chorioretinopathy (central serous retinopathy [CSR]); Retinal 
detachment; Retinal tear; Vision blurred; Visual impairment; 
Vitreous floaters; Photopsia; Eye disorder; Photophobia; Retinal 
vein occlusion (RVO); Detachment of retinal pigment epithelium 
(Retinal pigment epithelial detachment [RPED]).
Hepatotoxicity
Drug-induced liver injury; ALT increased; AST increased.
Muscular toxicity
Blood creatine phosphokinase increased; Musculoskeletal pain; 
Muscular weakness; Myalgia; Rhabdomyolysis; Myoglobin blood 
increased; Myoglobin urine present; Acute kidney injury; 
Myopathy.
Cardiac toxicity
Ejection fraction decreased; Oedema peripheral; Peripheral swelling; 
Oedema; Left ventricular dysfunction; Ventricular dysfunction.
Physeal dysplasia
Metaphyseal dysplasia; Multiple epiphyseal dysplasia; Arthralgia; 
Joint stiffness; Joint hyperextension; Gait disturbance; Short stature.
Choking on the capsule
Choking; Retching.
AESI, adverse event of special interest; MedDRA, Medical Dictionary for Regulatory Activities. 

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8.5
Overdose
For this study, any dose of selumetinib greater than the assigned dosage will be considered an 
overdose. There is currently no specific treatment in the event of overdose of selumetinib, and 
possible symptoms of overdose are not established.
Overdose should be followed up and treated with appropriate supportive care until recovery. 

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
Investigator or other site personnel should inform appropriate AstraZeneca representatives 
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 provided to the AstraZeneca Patient Safety data entry site within one or 5 calendar 
days for overdoses associated with an SAE (see Section 8.4.9) and within 30 days for all other 
overdoses.
8.6
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological Samples 
see Appendix C.
Human blood samples will be disposed as soon as possible after the test outlined in this document is 
complete.
Pharmacokinetic or PD samples may be disposed of or anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled PK or PD samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the Clinical 
Study Report.
Remaining unused PK or PD samples may be used for exploratory biomarker analysis as indicated 
in Section 8.7 and is subject to agreement in the ICF and also according to local requirements. 
8.6.1
Pharmacokinetics

Blood samples will be collected for measurement of plasma concentrations of selumetinib and 
N-desmethyl selumetinib as specified in the SoA (Table 2).

Samples may be collected at additional time points during the study if warranted and agreed 
upon between the Investigator and the sponsor, e.g., for safety reasons. The timing of sampling 

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may be altered during the course of the study based on newly available data (eg, to obtain data 
closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring. 
∀
Plasma samples will be used to analyse the PK of selumetinib and N-desmethyl metabolite.
Samples collected for analyses of study intervention (plasma) concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the study.
∀
Pharmacokinetic samples will be analysed at bioanalytical test sites operated by or on behalf of 
AstraZeneca. Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual.
8.6.1.1
Collection of Samples
Blood samples will be collected for measurement of selumetinib and N-desmethyl selumetinib as 
shown in Table 15.
Table 15
Pharmacokinetic Sampling Schedule
Time a
Cycle 1, Day 1 b
Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose
Cycle 2, Day 1 c
Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose
Cycle 5, Day 1 
Pre-dose
Cycle 13, Day 1
Pre-dose
Cycle 25, Day 1
Pre-dose
Transition from 
granule to capsule 
formulation d
Pre-dose, 0.5, 1.5, 3, 6, and 10-12 hours post-dose
a.
Pre-dose within 10 minutes prior to dosing. Time allowance for samples 1, 2, 3 and 4 hours post-dose: 
± 15 minutes, 6 and 8 hours post-dose ± 30 minutes. On Cycle 2, Day 1, the second dose of selumetinib should be 
taken after the 12 hour sample.
b.
Single dose (morning only) will be administered on Cycle 1, Day 1; bid continuous dosing will start from Cycle 1, 
Day 2.
c.
For operational reasons, the pharmacokinetic sampling on Cycle 2, Day 1 can take place on any day between 
Cycle 1, Day 24 and Cycle 2, Day 8 as long as the participant has received 3 consecutive days of bid dosing 
immediately prior to the PK day. Every effort should be made to conduct PK sampling within the window. 
However, if for unforeseen reasons this is not possible, PK sampling can be performed at any time from 7 days 
prior to Cycle 2, Day 1 to end of Cycle 3 provided the participant has received 3 consecutive days of dosing 
immediately prior to the PK day. 
d.
Samples should be taken on Day 7 (range Day 4 to Day 14) as long as the participant has received 3 consecutive 
days of twice daily dosing with capsule formulation immediately prior to the PK day.
PK, pharmacokinetic.
8.6.1.2
Determination of Drug Concentration
Samples for determination of selumetinib and N-desmethyl selumetinib in plasma will be assayed 
by 
bioanalytical laboratories on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the analytical method used will be 
described in a separate bioanalytical report.
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Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of the 
test samples. The results from the evaluation, if performed, will be reported in a separate 
Bioanalytical Report.
8.6.2
Pharmacodynamics
Where possible, optional blood samples for exploratory analysis of pharmacodynamic biomarkers 
in PBMCs can be taken during Cycle 1, Day 1. This analysis includes, but may not be limited to, 
pERK inhibition. This would require additional blood volume on a PK profile day, in addition to the 
volume required for PK samples and for safety samples. In line with the European Condition 
requirement that blood volume should not exceed 1% of the total blood volume at any single time, 
the samples for pERK can only be collected only in patients ≥27 kg. For a patient that is 6 years old 
this would mean that they would have to be approaching the 98th percentile on the UK-WHO 
growth chart (UK WHO Growth Chart). It is therefore considered these samples would be collected 
only in the oldest and largest of children. Samples should be taken according to Table 16. 
Table 16
Pharmacodynamic Sampling Schedule
Visit
Time a
Cycle 1, Day 1
Pre-dose and 1, 3 and 18-24 hours post-dose
a.
Pre-dose within 10 minutes prior to dosing. Time allowance for samples 1 and 3 hours post-dose ± 15 minutes. 
8.7
Human Biological Sample Biomarkers
8.7.1
Collection of Mandatory Samples for Biomarker Analysis
There is no additional biomarker sample collection in this study.
8.7.2
Other Study-related Biomarker Research
Already collected PK or PD samples may be analysed to explore potential biomarkers, which may 
influence the progression of NF1 and inoperable PNs (and associated clinical characteristics) and/or 
identify participants likely to respond to selumetinib or may be surrogate markers of response. 
Exploratory biomarker analyses may include (but not limited to) phosphorylated ERK, cytokines, 
and/or quantification of RNA expression using quantitative RT-PCR, microarray, or other 
technology in blood, peripheral blood mononuclear cells, serum, or plasma to evaluate their 
association with observed responses to selumetinib. This analysis excludes genomic analysis, but 
targeted sequence analysis on genes involved in NF1 might be included. This biomarker research is 
subject to additional optional consent in the ICF.
For storage, re use, and destruction of biomarkers samples, see Section 8.6.
8.8
Optional Genomics Initiative Sample
Not applicable.

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8.9
Health Economics
Not applicable. 
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
No formal hypotheses will be tested. 
The primary PK objective of the study is to estimate the granule formulation single dose AUC0-12 
for the final recommended dose schema in paediatric participants aged ≥4 to < 7 years and aged ≥ 1 
to < 4 years and check the estimation with the capsule formulation single dose AUC0-12 at 
25 mg/m2 as observed in the pivotal safety and efficacy study SPRINT.  
9.2
Sample Size Determination
Global Cohorts (Cohorts 1 and 2)
Approximately 
 participants will be dosed in Cohorts 1 and 2 to achieve 
 evaluable participants 
at the recommended granule formulation dose schema, of whom at least 
participants will be aged 
≥ 1 to < 4 years (with at least aged < 2 years) and at least 
participants will be aged ≥ 4 to < 7 
years. A sample size of 
 participants will provide reasonable precision to characterise PK and 
safety.
At least 
 evaluable participants in each age group are required at the final recommended granule 
formulation dose schema. 
With a minimum of 
 evaluable participants in each age group and 
 evaluable participants in 
total, the numbers of participants in the 2 age groups will fall between a combination of 
 to a 
combination of 
 With sample sizes of 
 in an age group, the power to show that 
the 
% CI of the AUC0-12 geometric mean falls within the acceptance range 
-fold of the 
SPRINT AUC0-12 geometric mean; FDA Guidance 2014) will be 90%, 99.9% and > 99.9%, 
respectively. The power for two age groups falling within the acceptance range simultaneously will 
therefore be 90% × 99.9% ≈90% and 99.9% × 99.9% ≈99.9% for the
 combination and 
 
 combination, respectively. This sample size calculation assumes that there is a 
% difference 
in exposure between the granule and capsule formulation and assumes an inter-subject gCV% of 
% (Wang et al 2012). The choice of gCV% is based on observations from Study 89 (
%) and the 
SPRINT study (
%).
In the dose-finding phase of this study, the exposure AUC0-12 will be monitored on an ongoing 
basis. The minimum sample size for each cohort and the study may be re-estimated when 
evaluable participants in that cohort have provided acceptable PK exposures. The re-estimation 
will use the observed inter-subject gCV%. Table 17 below shows the minimum sample sizes 
required in each age group corresponding to different variability and different scenarios.
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Table 17
Sample Size Estimations based on Inter-subject gCV% and Expected 
Differences in AUC0-12 between SPRINKLE and SPRINT studies
Inter-subject gCV%
Difference in AUC0-12 between SPRINKLE and SPRINT studies
± 5%
± 10%
± 15%
AUC0-12, area under the concentration-time curve from time zero to 12 hours; CV, geometric coefficient of variation.
Japan Cohort
In addition to the Global Cohorts (Cohorts 1 and 2), a separate Japan Cohort of a minimum of 
evaluable Japanese participants aged ≥1 to < 7 years will be recruited in Japan.
An evaluable participant for PK and sample size calculations is defined as a participant with a PK 
profile on Day 1 (for an individual at least 6 samples during the 12-hour time period post first dose 
on Cycle 1, Day 1 and must include the 10-12 hour PK sample) without any important protocol 
deviations potentially impacting the PK results.
Note: “Enrolled” means a participant’s or their legally authorised representative (parent or 
guardian) and participant’s (if deemed appropriate as per local regulations) agreement to participate 
in a clinical study following completion of the informed consent process. Potential participants who 
are screened for the purpose of determining eligibility for the study, but do not receive selumetinib, 
are considered “screen failures”, unless otherwise specified by the CSP. 
9.3
Populations for Analyses
The populations are defined as shown in Table 18.
Table 18
Populations for Analysis
Population/Analysis set
Description
All Enrolled 
All participants who sign the ICF
Pharmacokinetic Analysis Set 
All participants who receive at least one dose of selumetinib and who have at 
least one post-dose quantifiable plasma concentration with no important protocol 
deviations
Safety Analysis Set
All participants who receive at least one dose of selumetinib
ICF, informed consent form.
Note: The PK data for the Japan Cohort will be summarised separately to the PK data for the Global 
Cohorts.
In the case of an important protocol deviation or events that may impact the quality of the data, 
affected PK data collected will be excluded from the summaries and statistical analyses, but will 
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still be reported in the study result listings. Important deviations will be listed and summarised in 
the Clinical Study Report. The study physician, pharmacokineticist, and statistician will agree on 
the strategy for dealing with data affected by protocol deviations or events that may impact the 
quality of the data before any statistical analysis is performed.
9.4
Statistical Analyses
The Statistical Analysis Plan will be finalised prior to database lock and will include a more 
technical and detailed description of the statistical analyses described in this section. This section is 
a summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
9.4.1
General Considerations
All study data, originally captured or derived, will be listed and summarised as appropriate.
In the rest of this section, the planned analyses are general and will be performed both for Global 
Cohorts and Japan Cohort. If an analysis is particular for one population (for example the 
granule/capsule PK exposure comparison), it will be stated so.
The PK analysis will be based on the PK analysis set. Plasma concentrations and all PK parameters 
derived from plasma concentrations will be listed and summarised. In the case of an important 
protocol deviation or event, affected PK data may be excluded from the summaries and statistical 
analyses, but will still be included in the data listings. The PK exclusion decision will be 
documented by the PK scientist including the reason(s) for exclusion. PK analyses for the Japan 
Cohort will be presented separately from the Global Cohorts. 
The safety analyses will be based on the safety analysis set. Continuous variables will be 
summarised using descriptive statistics (n, mean, SD, minimum, median, maximum). Categorical 
variables will be summarised in frequency tables (frequency and proportion). There are no 
statistical analyses other than summary statistics planned for safety endpoints. 
Participant disposition will be presented for all enrolled participants. Protocol deviations will be 
discussed at the data review meeting before database lock and will focus on deviations from the 
CSP including (but not limited to):

Inclusion/exclusion criteria deviations

Dosing deviations

Time window deviations for PK or safety assessments

Receiving prohibited concomitant medications

Other procedural and study conduct deviations
Efficacy evaluation will be based on the safety set using PN response data from volumetric MRI.
All statistical analyses and production of tables, figures and listings will be performed using 

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Statistical Analysis Software (SAS) ® Version 9.3 or later.
There will be 3 analysis time points:
1
Pharmacokinetic, dose-finding, and primary safety analysis:
#
A DCO (DCO1) and analysis will occur after all participants have had the opportunity to 
complete 3 cycles of treatment. This primary analysis will confirm the recommended 
granule formulation dose schema and assess PK, safety/tolerability and palatability. The 
timing of DCO1 may be different for the Global Cohorts (Cohorts 1 and 2) from the Japan 
Cohort, based on their date of Last Subject In.
#
The PK samples will be analysed on a regular basis to inform SRC. It is expected that 
single and multiple dose PK from all participants dosed with selumetinib would be 
available within 3 months of the last participant being dosed; at this point, all participants 
will have palatability data available and a minimum of 3 months of safety data.
2
Safety and efficacy of the granule formulation: 
#
A DCO (DCO2) and analysis will occur after all participants in the study (Global and 
Japan Cohorts) have had the opportunity to complete 25 cycles (or terminated 
selumetinib); this analysis will provide additional PK and safety/tolerability data, as well 
as palatability and efficacy data.
#
Efficacy analyses will be performed, including: ORR (assessed by ICR and investigator), 
 and COAs.
3
Long term safety follow-up for participants until they reach the age of 5 years or commence an 
alternative systemic NF1-PN treatment, whichever is the earlier: 
#
A final analysis will occur when all participants in the study (Global and Japan Cohorts) 
have had the opportunity to complete their last assessment in the study, including the 
safety follow-up for participants aged < 5 years.
#
All of the safety/tolerability analyses will be updated with the data captured after the DCO 
for the analysis shown in bullet point 2 above (safety and efficacy of the granule 
formulation).
9.4.2
Pharmacokinetic Assessments 
9.4.2.1
Primary and Secondary Endpoint(s)
Pharmacokinetic parameters will be derived for selumetinib using plasma concentrations. 
Selumetinib PK is not time-dependent and minimal accumulation was observed in adult or 
paediatric participants following chronic bid dosing. In addition, sample size calculations have been 
based on single dose PK variability from Study 89. Therefore, single dose AUC0-12 will be used as 
the primary PK variable for comparison with SPRINT data.
Summary statistics including gCV%, arithmetic mean (SD), median (min, max) will be provided by 
age and BSA group. The geometric mean is calculated as the exponential of the arithmetic mean 
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calculated using log-transformed data. The gCV% is calculated as 100 exp푠 −1 where s is the 
SD of the log-transformed data.
At the final sample size for the recommended dose schema in the Global Cohorts (Cohorts 1 and 2), 
the AUC0-12 geometric mean and 
% CI (from one sample t-statistic) will be determined for each 
age group and overall. If the 
% CI falls within 
% of the geometric mean AUC0-12 
observed in the pivotal safety and efficacy study, SPRINT, then it will be concluded that 
comparable exposure to selumetinib was observed across the age groups.
Box and whisker plots of observed AUC0-12 will be produced for comparison to the target range 
for the capsule formulation determined from SPRINT.
9.4.2.2
Secondary Endpoint(s)
Pharmacokinetic parameters will be derived for selumetinib and N-desmethyl selumetinib using 
plasma concentrations.
The following secondary PK parameters will be calculated, if appropriate, and if data allow:
∀
Plasma concentrations and PK parameters of selumetinib including, but not limited to:
#
AUC0-12 derived after multiple dose administration.
#
Cmax, AUC0-6, AUClast, CL/F, tmax, tlast; derived after single and multiple dose 
administration.
#
AUC0-24, Vz/F and t½λz after single dose administration. 
#
Rac Cmax, Rac AUC0-12, and Vss/F derived after multiple dose administration.
∀
Plasma concentrations and PK parameters of N-desmethyl selumetinib, including, but not 
limited to:
#
Cmax, AUC0-6, AUC0-12, AUClast, tmax, tlast derived after single and multiple dose 
administration. 
#
Rac Cmax and Rac AUC derived after multiple dose administration.
#
Parent-to-metabolite ratio for AUC0-6, AUC0-12 and AUC0-24 (single dose only) and 
Cmax derived after single and multiple dose administration. 
For the participants that transition to capsule formulation BSA normalised AUC0-6, AUC0-12, 
AUClast and Cmax will be determined following multiple dose administration of granule and 
capsule formulation. The ratio of granule:capsule formulation will be determined for each of these 
parameters, the data will be listed and summarised.
Summary statistics including geometric mean (geometric CV%), arithmetic mean (SD), median 
(min, max) will be provided by formulation, analyte and period for AUC0-6, AUC0-12, AUC0-24, 
AUClast and Cmax. For CL/F, Rac Cmax, Rac AUC0-12 and for the comparisons of BSA 
normalised PK parameters for capsule and granule only arithmetic mean (SD) and median (min, 
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max) will be presented. For tmax and tlast, only median (min, max) will be presented. For CL/F, 
t½λz, Vss/F and Vz/F only arithmetic mean (SD) and median (min, max) will be presented. 
Selumetinib and N-desmethyl selumetinib plasma concentrations and PK parameters will be listed 
and summarised by formulation, age group, dose group and BSA group for Cycle 1 Day 1, Cycle 2 
Day 1 and capsule dosing Day 7 (range Day 4 to 14). 
Geometric mean (± geometric SD) plasma concentration versus nominal sampling time will be 
plotted in a linear and semi-logarithmic scale for each PK sampling period and with a separate plot 
for each analyte. Exploratory analyses may be conducted to explore the relationship between 
exposure or PK parameters, PBPK simulations and the pharmaceutical properties of the API and/or 
the formulation.
Box and whisker plots of observed PK parameters will be produced for comparison to the target 
range for the capsule formulation determined from SPRINT.
Further data presentation and reporting details will be provided in the Statistical Analysis Plan.
Details of 
 analyses will be described in the 
 
finalised before database lock. The 
 analyses will be presented separately 
from the main Clinical Study Report.
9.4.2.3
Exploratory Analyses
Exploratory analyses may be conducted, for example, using 
 
and on the 
 of the 
 and/or the
.
9.4.3
Safety
9.4.3.1
Primary Endpoint(s)
Safety and tolerability will be evaluated in terms of AEs, palatability, clinical safety laboratory 
assessments, physical examination, weight, vital signs, ECG, ECHO, ophthalmologic assessment, 
knee (or wrist) MRI/X-ray, and performance status.
All safety assessments will be listed. 
All AEs will be coded using MedDRA. A treatment emergent AE is defined as an AE which starts, 
or worsens, after the first dose of study drug. Treatment-emergent AEs will be summarised 
including tabulations by causality and severity. All tabulations will be presented by system organ 
class and preferred term. Serious AEs and AEs leading to treatment discontinuation will be listed 
separately.
For laboratory assessments, weight, vital signs, physical examination, ECG, ECHO, ophthalmologic 
assessment, knee (or wrist) MRI/X-ray, and performance status, summary statistics will be provided 
as appropriate. Continuous variables will be summarised by number, mean, SD, minimum, median, 
maximum. Categorical variables will be summarised in frequency tables (frequency and 
proportion). Only descriptive statistics are planned for safety endpoints. 
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For haematology and clinical chemistry, changes from baseline will also be presented in summary 
tables. Grade shift tables (from baseline to maximum on treatment) will also be presented. Change 
from baseline or grade shift may also be provided for other safety assessments if appropriate.
9.4.3.2
Exploratory Safety Endpoints
Exploratory safety endpoints include 
 
and the 
 All data will be listed by visit. Continuous 
variables will be summarised by number, mean, SD, minimum, median, maximum. Categorical 
variables will be summarised in frequency tables (frequency and proportion).
9.4.4
Efficacy Endpoints
Efficacy endpoints include PN responses from volumetric MRI and COAs. Plexiform neurofibroma 
responses from on-treatment MRI scans will be considered as primary estimands and responses 
from all MRI scans (regardless of treatment discontinuation) will be considered as supplementary 
estimands.
Efficacy analysis will be conducted on the safety set for ORR; 
, and COAs as 
defined in Section 8.1. For all efficacy analysis, missing data will not be imputed (will be treated as 
missing or censored).
9.4.4.1
Secondary Efficacy Endpoint
Objective response rate is a secondary endpoint which will be estimated together with 95% CIs 
constructed using the Clopper-Pearson method (Clopper and Pearson 1934). 
9.4.4.2
Exploratory Efficacy Endpoints
 are exploratory endpoints. Median and 95% CI will be calculated using 
 will be provided for each of these endpoints.
The following COAs are exploratory endpoints which will be summarised for the Safety Set:
∀
∀
∀
∀
∀
∀
 will be provided if appropriate.
9.4.5
Other Analyses 
Demographic and disposition data, as well as exposure data, will be listed and summarised. The 
exposure summary will include duration of treatment (total and actual) and treatment interruptions 
in each treatment period. Demographic and exposure data will be presented using the Safety 
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Analysis Set. Disposition data will be presented for all enrolled participants.
Prior and concomitant medications will be listed for the Safety Analysis Set.
Compliance with questionnaires completed by parent/guardian or participant will be summarised as 
appropriate; details will be provided in the Statistical Analysis Plan. 
pERK inhibition in PBMCs will be summarized by scheduled sample time points and change from 
pre-dose for the subset of participants who provide pERK samples.
Biomarker exploratory analyses will be described in a separate analysis plan and will be reported 
outside the Clinical Study Report in a separate report. The results of this biomarker assessment will 
be reported as an addendum, and/or separately in a scientific report or publication. The results of 
this biomarker assessment may be pooled with biomarker data from other studies with the study 
intervention to generate hypotheses to be tested in future research.
9.5
Interim Analyses 
There is no interim analysis planned for this study.
9.6
Data Monitoring Committee
Not applicable. 
Safety Review Committee
An SRC will be formed for the dose-finding phase to evaluate the safety, tolerability and PK data of 
the granule formulation dose schema for selumetinib. Section 6.1.2 provides information on SRC 
reviews and decision points. Detailed information will be provided in the SRC charter. 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the CSP and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013 and CIOMS International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, revised protocol, ICF, Investigator Brochure, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO but 
the accountability remains with AstraZeneca.

The Investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local regulations
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.

AstraZeneca has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
AstraZeneca will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators.

For all studies except those utilising medical devices, Investigator safety reports must be 
prepared for SUSAR according to local regulatory requirements and sponsor policy and 
forwarded to Investigators as necessary.

Adherence to European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations.

An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from AstraZeneca will review and then 

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file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
Prompt notification by the Investigator to AstraZeneca of any (potential) serious breach of the 
protocol or regulations is essential so that legal obligations and ethical obligations are met.

A “serious breach” means a breach likely to affect to a significant degree the safety and rights 
of a participant or the reliability and robustness of the data generated in the clinical trial.
AstraZeneca will comply with country-specific regulatory requirements relating to serious breach 
reporting to the regulatory authority, IRB/IEC, and Investigators.

Where the EU Clinical Trials Regulation 536/2014 applies, AstraZeneca has in place processes 
to enter details of serious breaches into the European Medicines Agency CTIS. It is important 
to note that redacted versions of serious breach reports will be available to the public via CTIS.
If any (potential) serious breach occurs in the course of the study, Investigators or other site 
personnel will inform the appropriate AstraZeneca representatives immediately after they become 
aware of it.
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
The Investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to identify 
the occurrence of a (potential) serious breach.

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, through 
the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are also 
responsible for providing information on financial interests during the course of the study and for 
one year after completion of the study.
A 3
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the participant 
and his/her legally authorised representative (parent/guardian) and answer all questions 
regarding the study.

The participant’s legally authorised representative (defined as parent or guardian) and 
participant (if deemed appropriate per local regulation) must be informed that their 
participation is voluntary and they are free to refuse to participate and may withdraw their 

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consent at any time and for any reason during the study. The participant’s legally authorised 
representative (defined as parent or guardian) and participant (if deemed appropriate as per 
local regulations) will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
Participants may also be required to sign a statement of assent if deemed appropriate as per 
local regulations.

The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.

The participant’s legally authorised representative and participant (if deemed appropriate as per 
local regulations) must be re-consented to the most current version of the ICF/assent during 
their participation in the study.

A copy of the ICF/assent must be provided to the participant’s legally authorised representative 
and participant (if deemed appropriate as per local regulations). 
In cases where a participant is rescreened, another ICF is not required to be signed if the rescreening 
occurs within 28 days from the previous ICF signature date.
The ICF will contain a separate section that addresses and documents the collection and use of any 
mandatory and/or optional human biological samples. The Investigator or authorised designee will 
explain to each participant the objectives of the analysis to be done on the samples and any potential 
future use. Participants will be told that they are free to refuse to participate in any optional samples 
or the future use and may withdraw their consent at any time and for any reason during the retention 
period.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.

The participant’s legally authorised representative (parent or guardian) and participant (if 
deemed appropriate as per local regulations) must be informed that the participant’s personal 
study-related data will be used by the sponsor in accordance with local data protection law. The 
level of disclosure and use of their data must also be explained to the participant’s legally 
authorised representative (parent or guardian) and participant (if deemed appropriate as per 
local regulations) in the informed consent.

The participant’s legally authorised representative (parent or guardian) and participant (if 
deemed appropriate as per local regulations) must be informed that the participant’s medical 
records may be examined by Clinical Quality Assurance auditors or other authorised personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
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
The participant’s legally authorised representative (parent or guardian) and participant (if 
deemed appropriate as per local regulations) must be informed that data will be collected only 
for the business needs. We will only collect and use the minimum amount of personal data to 
support our business activities and will not make personal data available to anyone (including 
internal staff) who is not authorised or does not have a business need to know the information. 

The participant’s legally authorised representative (parent or guardian) and participant (if 
deemed appropriate as per local regulations) must be informed that in some cases their data 
may be pseudonymised. The General data Protection Regulation (GDPR) defines 
pseudonymisation as the processing of personal data in such a way that the personal data can no 
longer be attributed to a specific individual without the use of additional information, provided 
that such additional information is kept separately and protected by technical and organisational 
measures to ensure that the personal data are not attributed to an identified or identifiable 
natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed.

In compliance with applicable laws, the Data Controller1 for the processing activity where the 
personal data breach occurred (AstraZeneca or respectively the site), will notify the data 
protection authorities without undue delay within the legal terms provided for such notification 
and within the prescribed form and content.

Whilst AstraZeneca has processes in place to deal with personal data breaches it is important 
that investigators that work with AstraZeneca have controls in place to protect patient data 
privacy.
The Investigator should have a process in place to ensure that:

allow site staff or service providers delegated by the investigator/institution to identify the 
occurrence of a (potential) personal data breaches.

Any (potential) personal data breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.
                                               
1 The data controller determines the purposes for which and the means by which personal data is 
processed, as defined by the European Commission

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AstraZeneca and the site must demonstrate that they:

have taken all necessary steps to avoid personal data breaches and 

have undertaken measures to prevent such breaches from occurring in the first place and to 
mitigate the impact of occurred data breaches (eg, applying encryption, maintaining and 
keeping systems and IT security measures up-to-date, regular reviews and testing, regular 
training of employees, and developed security policies and standards).

where possible, have developed an internal data breach reporting and investigation process and 
internal protocols with guidance on how to respond swiftly and diligently to the occurrence of a 
personal data breach.

where it has not been possible to develop an internal data breach reporting and investigation 
process, the site follows AstraZeneca’s instructions.
Notification of personal Data Breach to participants:

notification to participants is done by the site for the data breaches that occurred within the 
processing activities for which the site is the Data Controller and for data breaches occurred 
within the processing activities of AstraZeneca as the Data Controller, the notification is done 
in collaboration with the site and is performed by the site and/or Principal Investigator, acting 
on behalf of AstraZeneca, so that AstraZeneca has no access to the identifying personal 
information of the participants. The site and/or Principal Investigator shall conduct the 
notification by contacting the participants using the information that they gave for 
communication purposes in clinical research.

If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course after 
discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the processing 
activity where the breach occurred, it will be responsible for the notification to data protection 
authorities and, if applicable, to participants. If the personal data breach needs to be notified to 
the participants, the notification to participants is done in collaboration with the site and is 
performed by the site and/or Principal Investigator, acting on behalf of the Sponsor, so that 
AstraZeneca has no access to the identifying personal information of the participants.

If a personal data breach involving an AstraZeneca's representative device (i.e., Study Monitor 
laptop), AstraZeneca representative will provide AstraZeneca with all of the information 
needed for notification of the breach, without disclosing data that allows AstraZeneca directly 
or indirectly to identify the participants. The notification will be done by AstraZeneca solely 
with the information provided by the Study Monitor and in no event with access to information 
that could entail a risk of re-identification of the participants. If the data breach must be notified 
to the data subjects, the notification will be done directly by the Study Monitor in collaboration 
with the site and/or Principal Investigator, acting on behalf of the Sponsor, so that AstraZeneca 
has no access to the identifying personal information of the participants. The contract between 
AstraZeneca and the Study Monitor shall expressly specify these conditions.

The contract between the site and AstraZeneca for performing the clinical research includes the 
provisions and rules regarding who is responsible for coordinating and directing the actions in 

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relation to the breaches and performing the mandatory notifications to authorities and 
participants, where applicable.
A 5
Committees Structure
N/A
A 6
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS within a 
year from global End of Trial Date in all participating countries, due to scientific reasons, as 
otherwise statistical analysis is not relevant.
A description of this clinical study will be available on www.astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov and https://euclinicaltrials.eu/ as will the summary of the main 
D1346C00004 study results when they are available. The clinical study and/or summary of main 
D1346C00004 study results may also be available on other websites according to the regulations of 
the countries in which the main D1346C00004 study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF.

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan.

AstraZeneca or designee is responsible for medical oversight throughout the conduct of the 
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. Monitoring details describing clinical reviews of study data from a medical 
perspective are included in more detail in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 

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being conducted in accordance with the currently approved CSP and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for a minimum of 25 years after study archiving or as required by 
local regulations, according to the AstraZeneca Global retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Trial Master File and Investigator 
Site File.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first participant screened is considered the first act of recruitment and will be the study start 
date.
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. 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 CSP, the requirements of the IRB/IEC or local 
health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development

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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant therapy 
and/or follow-up. All data available for the participant at the time of discontinuation must be 
recorded in the eCRF together with the reason for the discontinuation.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.

The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant 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 (eg, 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 study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-up), 
that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Life-threatening
‘Life-threatening’ means that the participant 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 participant’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 an SAE, 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 
participant was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 

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situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may require 
medical treatment to prevent one 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
Intensity Rating Scale:
The grading scales found in the revised NCI CTCAE Version 5.0 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 can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov). The applicable version of CTCAE should be 
described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 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 Appendix B 2.
B 3
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 participant actually received the suspect drug? 
Did the AE occur in a reasonable temporal relationship to the administration of the suspect 
drug?

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?

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
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 rechallenge.

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 recognised 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 judgment. With no available facts or arguments to suggest a causal relationship, 
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.
B 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an IMP or AstraZeneca NIMP that either causes harm to the participant or has 
the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related failure 
while the drug is in control of the study site staff or participant.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

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
Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to the 
participant

Drug not administered as indicated, eg, wrong route, dose (error greater than ± 10%) or wrong 
site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a solid 
tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medication 
error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, non-
therapeutic excessive use of IMP/study intervention or AstraZeneca NIMP for a perceived reward or 
desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to the 
DES using the Drug Abuse Report Form. This form should be used both if the drug abuse happened 
in a study participant or if the drug abuse regards a person not enrolled in the study (such as a 
relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or a 
person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of getting high.
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorised product 

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information, or for unauthorised IMPs/study interventions or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol, and includes deliberate administration of the product by 
the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to the 
DES using the Drug Misuse Report Form. This form should be used both if the drug misuse 
happened in a study participant or if the drug misuse regards a person not enrolled in the study 
(such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol that 
it must be swallowed whole

Only half the dose is taken because the study participant feels that they were feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and records 
relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until used 
or disposed of or until further shipment and keeps record of receipt of arrival and onward shipment 
or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through internal 
procedures, monitoring of study sites, auditing or process checks, and contractual requirements of 
external laboratory providers.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner. 
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site or 
destroyed at the end of the retention period as described in the informed consent.
If the participant’s legally authorised representative (parent or guardian) and/or participant (if
deemed appropriate as per local regulations) withdraws consent to the use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The Investigator:

Ensures the participant’s legally authorised representative (parent or guardian) and/or 
participant’s (if deemed appropriate as per local regulations) withdrawal of informed consent to 
the use of donated samples is highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the study site, 
are immediately identified, disposed of as appropriate, and the action documented.

Ensures the participant’s legally authorised representative (parent or guardian) and/or 
participant (if deemed appropriate as per local regulations) and AstraZeneca are informed about 
the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the withdrawn 

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consent immediately and that samples are disposed of or repatriated as appropriate, and the action is 
documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to UN 2900.
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, C, D, and E viruses. They are 
assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are unlikely 
to cause disease in humans or animals are not subject to these Regulations unless they meet the 
criteria for inclusion in another class.

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 (https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-
60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification for 
the dry-ice content.

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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law
D 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
PHL cases and HL cases. 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 participant meets potential 
PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria could 
be met by an elevated ALT from a central laboratory and/or elevated TBL from a local laboratory. 
The Investigator will also review AE data (for example, for AEs that may indicate elevations in 
liver biochemistry) for possible PHL events.
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. Hy’s Law 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than DILI caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
SAEs and AEs according to the outcome of the review and assessment in line with standard safety 
reporting processes.
D 2
Definitions
Potential Hy’s Law
Aspartate aminotransferase or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during 
the study following the start of study medication irrespective of an increase in ALP.
Hy’s Law
Aspartate aminotransferase or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other 
reason, other than the IMP, 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 (i.e., on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases

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In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination:

Alanine aminotransferase ≥3 × ULN

Aspartate aminotransferase ≥3 × ULN

Total bilirubin ≥2 × ULN
Local Laboratories:
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 participant meets PHL criteria (see Section D 2 for definition) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in the 
CSP.
D 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within one day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the Investigator is not required to 
submit a PHL SAE unless there is a significant change# in the participant’s condition.

The Medical Monitor contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) and the 
continuous review of data.

Subsequent to this contact the Investigator will:

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
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Medical Monitor. 

Complete the three Liver eCRF Modules as information becomes available.
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or TBL) 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 
Medical Monitor if there is any uncertainty.
D 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.
As soon as possible after the biochemistry abnormality was initially detected, the Medical Monitor 
contacts the Investigator in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP, to ensure 
timely analysis and reporting to health authorities within 15 calendar days from date PHL criteria 
was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also 
be involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the appropriate 
eCRF.

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE and AE 
eCRFs accordingly with the new information (reassessing event term; causality and seriousness 
criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.

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
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 15 calendar days 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:

Provides any further update to the previously submitted SAE of PHL (report term now ‘Hy’s 
Law case’) ensuring causality assessment is related to IMP and seriousness criteria is medically 
important, according to CSP process for SAE reporting.

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 
still met. Update the previously submitted PHL SAE report following CSP process for SAE 
reporting, according to the outcome of the review and amending the reported term if an 
alternative explanation for the liver biochemistry elevations is determined.

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Appendix E
Guidance for Management of Specific Adverse Events
E 1
Management of Left Ventricular Ejection Fraction Reduction 
(asymptomatic) or Left Ventricular Systolic Dysfunction
ECHO, echocardiogram; LLN, lower limit of normal per local institution or site; LVEF, left ventricular ejection 
fraction.

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E 2
Management of Creatine Kinase Elevation
CK, creatine kinase; CTC Common Terminology Criteria for Adverse Events

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E 3
Management of Retinal Pigment Epithelial Detachment, Central 
Serous Retinopathy and Retinal Vein Occlusion 
CSR, central serous retinopathy; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion

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E 4
Management of Diarrhoea
CTC. Common Terminology Criteria for Adverse Events

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E 5
Management of New or Worsening Dyspnoea
BNP, brain natriuretic peptide; CT, computed tomography; ECG, electrocardiogram; Hb, haemoglobin; ILD, interstitial 
lung disease; NF1, neurofibromatosis type 1; P-A, posterior-anterior, PN, plexiform neurofibroma; WBC, white blood 
cell

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E 6
Management of Participants with Rash

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E 7
Oral Care Management for Events of Oral Mucositis and Dry Mouth
E 8
Management of Paronychia
CTC, Common Terminology Criteria for Adverse Events
Oral care guidelines for events of oral mucositis and dry mouth
•
Patients should be encouraged to follow a daily oral health care regimes, both before and during treatment with selumetinib. 
•
Patients with a healthy mouth may use non alcoholic mouthwash 4 to 6 times daily (e.g. after each meal), or according to the 
instructions, during the study. 
•
Saline mouthwashes (Sodium chloride 0.9%) are preferred to alcohol-based mouth washes in cases of stomatitis, and should 
be used at a different time than toothbrushing (e.g. after tea).
•
Use of a mouthwash immediately after selumetinib intake is recommended if possible. 
•
The tongue can be gently brushed (if not sore) with a soft toothbrush. 
•
Patients with, or at risk of, stomatitis should not use commercial/over-the-counter mouthwashes because of the alcohol content 
and astringency. Chlorhexidine mouthwashes are not recommended for the treatment of established stomatitis. 
•
The mouth should be regularly inspected by the patient and healthcare professionals. 
•
Teeth should be brushed twice daily with a fluoride toothpaste and soft toothbrush, in the morning before breakfast and last 
thing in the evening before bed, about 30 minutes after eating. The toothbrush should be replaced regularly (at least every 3
months). Patients with stomatitis should change their toothbrush every 4 - 6 weeks.
•
Consider culture to rule out herpes simplex.
•
Consider treating stomatitis at an early stage (CTCAE grade 1) or as soon as the patient complains of a sore mouth. Consider 
using an oral topical analgesic, with or without topical steroids, depending on the patient’s clinical condition and the local 
standard medical practice.

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E 9
Paronychia Treatment Recommendations
CTCAE, Common Terminology Criteria for Adverse Events
Adverse event
Treatment recommendations
Paronychia*
CTCAE grade 1
Treat the affected area by soaking in vinegar solution twice daily (1 part vinegar to 2 parts water) + 
Topical Antibiotic mupirocin twice daily.
CTCAE grade 2
Treat the affected area by soaking in vinegar solution twice daily (1 part vinegar to 2 parts water)  + 
Systemic antibiotic (Keflex, Clindamycin)+ high potency steroid (0.05% clobetasol ointment covered 
with saran wrap OR flurandrenolide tape (cordran tape) applied at bedtime. This should be removed in 
morning.
CTCAE grade 3
If severe, seek consult for incision & drainage or surgical management.  
*If granulation tissue present, consider use of silver nitrate under supervision.
For patients who do not undergo drainage, silver nitrate may be used, as well as topical bactroban, steroids, and/or antifungals. 
Silver nitrate is only of value when there is open inflamed skin or granulation tissue (e.g. pyogenic-granuloma-like lesions). If the 
periungual skin is swollen but intact (whether infectious or non-infectious), silver nitrate is not recommended. 
Patients should be cautioned to avoid trauma to the area. Podiatry consult may be considered for partial nail removal.
Patients who undergo incision and drainage and are found to have no infectious organisms on culture, should be treated as 
above. If infection is identified, patients may be treated with systemic antibiotics (oral tetracyclines).
If paronychia recurs or develops in other fingers or toes, Flurandrenolide (e.g. Cordran) tape or topical steroid cream such as 
triamcinolone can be used in the morning and Bactroban and Nizoral topical ointments in the evening.

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Appendix F
Blood Pressure
Blood pressure ≤ the 95th percentile for age, height, and gender is required for enrolment. Because 
measurement accuracy is dependent on the use of proper BP cuff size, BP cuff should be selected as 
follows:

Infant 8 to 11 cm.

Child 12 to 16 cm.

Small adult 17 to 22 cm.

Adult 23 to 33 cm.
Table F19
Blood Pressure Levels for Children by Age and Height Percentile – Blood 
Pressure for Boys
Age 
years
BP 
percentile
Systolic BP (mmHg)
Diastolic BP (mmHg)
Percentile of height
Percentile of height
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
98
99
101
103
104
106
106
54
54
55
56
57
58
58
2
95th
101
102
104
106
108
109
110
59
59
60
61
62
63
63
3
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
4
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
15
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
≥ 17
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
BP, blood pressure.
Source: National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and 
Adolescents 2004.

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Table F20
Blood Pressure Levels for Children by Age and Height Percentile – Blood 
Pressure for Girls
Age 
years
BP 
percentile
Systolic BP (mmHg)
Diastolic BP (mmHg)
Percentile of height
Percentile of height
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
100
101
102
104
105
106
107
56
57
57
58
59
59
60
2
95th
102
103
104
105
107
108
109
61
62
62
63
64
65
65
3
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
4
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
≥17
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
BP, blood pressure.
Source: National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and 
Adolescents 2004.
Table F21
New York Heart Association Classification
New York Heart Association grading
Metabolic equivalent a
Class I
No limitations. Ordinary physical activity does not cause undue fatigue, 
dyspnoea, or palpitations (asymptomatic left ventricular dysfunction).
> 7
Class II
Slight limitation of physical activity. Ordinary physical activity results in 
fatigue, palpitation, dyspnoea, or angina pectoris (mild congestive heart 
failure).
5
Class III
Marked limitation of physical activity. Less than ordinary physical 
activity leads to symptoms (moderate congestive heart failure).
2 to 3
Class IV
Unable to carry on any physical activity without discomfort. Symptoms 
of congestive heart failure present at rest (severe congestive heart failure).
1.6
a.
Metabolic equivalent is defined as the resting VO2 for a 40-year-old 70 kg man. Metabolic equivalent = 3.5 mL 
O2/min/kg body weight.
VO2, maximal oxygen uptake.

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Appendix G
Country-specific Requirements
OVERALL RATIONALE FOR THE ADDENDUM VERSION 6 (GERMANY):
Reason: To collect wet-ink signatures from the sponsor and national coordinating investigator 
for CSP Version 4.0, dated 14 February 2023 and to describe further changes in the CSP.
Section # and Name
Description of Change with Reason
Section 1, Protocol
summary; Section 1.3, 
Schedule of Activities 
(Table 2 and 3); Section
2.3.1, Risk assessment
(Table 4); Section 3, 
Objectives and Endpoints 
(Table 5); Section 8.2.7, 
Knee/Wrist MRI/X-ray; 
Section 9.4.3.1, Primary 
Endpoints
To assess the safety and tolerability of the selumetinib granule formulation 
(physeal dysplasia) just MRI scans will be used. X-ray scans will not be 
performed in Germany to reduce the patient burden. Those MRI scans can be 
performed in parallel to the PN assessments and there will be no risk of 
radiation for the patients.
Section 4.1.1, Study 
Conduct Mitigation during
This Section provides guidance during cases of civil crisis, natural disaster, or 
public health crisis. We specify that in Germany:

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Section # and Name
Description of Change with Reason
Study Disruptions Due to 
Cases of Civil Crisis, 
Natural Disaster, or Public 
Health; Appendix J, 
Changes Related to 
Mitigation of Study 
Disruptions Due to Cases 
of Civil Crisis, Natural 
Disaster, or Public Health 
Crisis

The extent of the actions is restricted to the COVID-19 pandemic

Duties overseen by the PI will not be delegated to Health Care 
Providers (HCP)/Third Party Vendors (TPV)

The PI or sub-investigators are responsible for the procedures such as 
performing blood draws, measuring vital signs, weight or height
Section 8.3.9, Reporting of 
Serious Adverse Events
With respect to SAE reporting described in this section, we clarify that the 
timespans (no later than 24 hours) do not apply. In Germany, SAE reporting has 
to be done immediately without undue delay after obtaining knowledge. Sites 
will be accordingly trained as per standard for clinical trial in Germany.
Section 1.3, Schedule of 
Activities; Section 8.1, 
Efficacy Assessments; 
Section 8.2.9, Clinical 
Safety Laboratory 
Assessments; Section 8.5, 
Human Biological samples
AstraZeneca has considered the burden on the study participants throughout the 
study design process. As requested by EC, summarised below is the patient 
burden caused by blood draws and MRI scans that should be minimal in this 
patient population.
In order to ensure the total blood volumes collected are appropriate for this 
patient population, AstraZeneca have referred to the European condition 
requirements.
The pharmacokinetic sample volume for each timepoint has been reduced in 
comparison to the previous adult studies considering the paediatric population.
With reference to the Blood Volume Guidelines V1.1, November 30, 2015, 
Stellenbosch University, Health Research Ethics Committee, the minimum BSA 
for inclusion in this study is 0.4m2, which equates to a weight of 7.5kg, it is 
therefore expected that these patients have a total blood volume of 560mL. As 
such, per the guideline, 5% (28mL) of total blood volume can be taken in a one-
off sampling, and within a 3 month time period. The first three months of the 
study include the most intensive sampling, in this period of time 14.0mL of 
blood will be taken which is lower than the maximum that can be taken per the 
guidance.
Additionally, in patients ≥27Kg, optional pharmacodynamic samples can be 
taken. It is expected that these patients have a total blood volume of 2080mL, 
5% of their total blood volume is therefore 104mL. Within the first 3 months of 
the study, 30.0mL of blood will be taken, which is lower than the maximum that 
can be taken per the guidance. AstraZeneca therefore confirm that the planned 
blood draws are within the Stellenbosch University, Health Research Ethics 
Committee guidance.
Blood volumes planned to be taken within the first 3 months (most 
intensive period) of the SPRINKLE study
Number of 
Timepoints
Volume 
per 
timepoint
Total Blood 
volume
Clinical chemistry 
& Haematology1
5
1.0mL
5mL

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Section # and Name
Description of Change with Reason
(Screening, cycle 1
day 1, cycle 1 day
15, cycle 2 day 1,
cycle 3 day1)
Troponin1
1
(Screening)
0.5
0.5mL
Pharmacokinetics
17
(9 on cycle 1 day 1,
8 on cycle 2 day 1)
0.5mL
8.5mL
Pharmacodynamics2
4
(Cycle 1 Day 1)
4.0mL
16.0mL
Total in first 3 months of study
Patients <27kg or ≥27Kg and don’t provide optional PD samples
14.0mL
Total in first 3 months of study
Patients ≥27Kg only that provide optional PD samples
30.0mL
1Safety samples are performed by local lab, therefore actual volumes will vary 
depending on the Institution. Each site is advised to minimise the amount of 
blood required.
2Optional pharmacodynamic samples which are collected only in patients
≥27Kg.
Investigators participating in the SPRINKLE study will use their discretion in 
the method of collecting biological samples to ensure that it is the least invasive 
manner for their patient. To minimise the number of punctures, the schedule of 
assessments is designed so that safety and PK samples can be taken at the same 
timepoint. PK samples can be taken using venous catheter to minimise the 
number of punctures, and AstraZeneca recommends that this is the approach 
Investigators use in order to minimise burden on the patient. Additionally sites 
are advised to use local measures such as local anaesthesia to reduce the 
discomfort of the blood sampling.
The intensive PK days of Cycle 1 Day 1, and Cycle 2 Day 1 require 9, and 8 
samples respectively to be taken within a 24 hour period. This number of 
samples is required so that we can estimate the pharmacokinetic profile and 
obtain the AUC values which is a primary objective of the study. On intensive 
PK sampling days, participants aged ≥ 1 to < 4 years can take selumetinib 
granules with or without food, but participants aged ≥ 4 to < 7 years are 
required to take selumetinib granules on an empty stomach. The flexibility for 
the younger children may lead to variability in the Cmax and tmax as food 
intake is known to reduce the rate of absorption of selumetinib. Adequate 
numbers of samples are therefore required to capture the tmax of the plasma 
concentrations under these differing conditions. The final statistical analysis 
will compare the SPRINKLE study AUC0-12 (patients aged
to
years) to the 
SPRINT study AUC0-12 (patients aged
to 
years) at the approved dose of 
25 mg/m2, and reducing the number of samples further could potentially lead to 
an underestimation of exposure which could compromise the study endpoint.
PPD
PPD
PPD
PPD

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Section # and Name
Description of Change with Reason
Patients must remain on the granule formulation until after they have completed 
their third cycle of treatment. Transition to the capsule formulation is 
encouraged in patients once they attain a BSA between 1.10 and 1.29 m2
because a large number of the available granule formulation strengths would be 
required to achieve the dosage. In patients that transition from granule 
formulation to capsule formulation, an additional intensive PK sampling day 
will be conducted on Day 7 of the capsule formulation. (PK samples may be 
taken between Day 4 and 14 if twice daily dosing has been maintained for 3 
days prior to the PK sample day, to allow flexibility). The intensive PK 
sampling on transition to capsule formulation requires 6 samples to be taken, in 
total approximately 3mL blood. The timepoints have been designed based on 
the known pharmacokinetic profile of the capsule formulation to ensure 
adequate samples are collected to calculate the PK parameters.
There are MRIs planned for both assessments of PN volume and monitoring for 
physeal dysplasia. All assessments of physeal dysplasia monitoring are 
scheduled at the same time as those for PN volume to minimise the patient 
burden. As such, per the schedule of assessments there will be MRIs every 4 
cycles in the first year, and every 6 cycles in the second year. In total there will 
be a maximum of 7 MRI assessments per patient. When receiving an alternative 
medical therapy for NF1-PN, MRI assessments in Germany could be conducted 
as often as every 3 months as standard of care. Therefore, the MRI assessment 
schedule implemented in SPRINKLE is in line, or slightly less burden than 
these patients would experience if receiving an alternative therapy.
The requirement for sedation or anaesthesia during the MRI will be determined 
by the treating Investigator based on the patient and done according with 
standard of care, in line with best practice.
Efficacy (Objective response rate) is a secondary endpoint, as required by the 
EMA Paediatric investigational plan. Additionally, time to response, duration of 
response, time to progression and progression free survival are exploratory 
endpoints. Therefore, in order to detect a confirmed response, or a progression it 
is important to conduct regular MRI scans. In the pivotal SPRINT Phase II 
Stratum 1 trial (patients aged 
years old), 42.4% (14/33) patients had onset
of response by 4 cycles from first dose, and 97.0% (32/33) had onset of
response by12 cycles. It is therefore expected that the majority of patients who 
have confirmed response in the SPRINKLE study, will demonstrate initial 
response within the first year of treatment. The proposed MRI scheduling (every 
4 cycles in the first year, followed by every 6 cycles in the second year)
balances the ability to characterise time to onset of response, demonstrate 
confirmation of a response with 2 consecutive MRI scans within a 2 year 
treatment period, whilst being mindful of patient burden. Additionally, a more 
frequent schedule during this first year is important for the treating Investigator 
to determine that the patient is receiving clinical benefit and should continue 
receiving selumetinib treatment.
The SPRINKLE study is based on a PK extrapolation strategy, whereby the 
extrapolated efficacy of the granule formulation will primarily be based on the 
observed selumetinib PK (exposure) matching that observed in the pivotal 
safety and efficacy study SPRINT (Gross et al 2020). The PK extrapolation 
approach uses fewer patients than a traditional Phase II or Phase III study 
design.
PPD

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Section # and Name
Description of Change with Reason
AstraZeneca and the SPRINKLE study PIs are committed to minimising the 
patient burden of participating in this study. Participation in this study does 
have an increased assessment burden, due to the necessary collection of 
pharmacokinetic samples mainly at the start of the study. However, 
participation in this study enables patients as young as 1 year-old with NF1 and 
symptomatic, inoperable PNs to receive treatment with an age-appropriate 
formulation of selumetinib without the need to fast instead of the capsule that 
requires fasting twice a day. This reduces the burden and duration of time for 
these young children to learn to swallow capsules whilst their PNs continue to 
grow and impact on their daily life. There is no alternative approved treatment 
for patients with NF1 and symptomatic inoperable PN who cannot swallow 
capsules.
Section 1.3, Schedule of 
Activities; Section 8.2.9, 
Clinical Safety Laboratory 
Assessments; Section 8.5, 
Human Biological samples
As requested by EC, it must be specified whether the mentioned number of 
35ml blood includes only the pharmacokinetic samples or the necessary safety 
laboratory as well.
The total amount of blood to be taken in the course of study (35mL) includes 
the planned safety laboratory samples as well as the pharmacokinetic tests that 
all patients will have. This does not include the optional pharmacodynamic 
samples that can only be collected in patients ≥27kg (See Section 8.5.2 of the 
CSP) or the pharmacokinetic samples that are collected only in patients if they 
transition from the granule to the capsule formulation (see section 8.5.1 of the 
CSP).
Section 1.1, Synopsis;
Section 6.7, Intervention 
after the End of the Study
As requested by the EC, we changed the wording in the synopsis to describe the 
follow-up treatment more precisely.
If selumetinib (capsule or granule formulation) is approved locally and 
reimbursed for use in paediatric patients with NF1 who have symptomatic, 
inoperable PN, participants should be switched to the commercial supply at the 
end of their participation in the study. However, if the participant is unable to 
access the commercial supply of selumetinib, and they are still receiving clinical 
benefit AstraZeneca and the investigator will ensure that the participant will be 
able to continue to receive selumetinib (capsule and granule formulation) if 
he/she is benefiting from treatment.

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Appendix H
Performance Status Scales
Table H22
Performance Status Criteria
Lansky Performance Status
Score
Description
100
Fully active, normal.
90
Minor restrictions in physically strenuous activity.
80
Active, but tires more quickly.
70
Both greater restriction of and less time spent in play activity.
60
Up and around, but minimal active play; keeps busy with quieter activities.
50
Gets dressed, but lies around much of the day; no active play, able to participate in all quiet play 
and activities.
40
Mostly in bed; participates in quiet activities.
30
In bed; needs assistance even for quiet play.
20
Often sleeping; play entirely limited to very passive activities.
10
No play; does not get out of bed.
Lansky performance scores are intended to be multiples of 10.

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Appendix I
Guidance Regarding Potential Interactions with Concomitant 
Medications
Throughout the study, participants should avoid changes to, or the addition of all concomitant 
medications, in particular any that may affect the metabolism of selumetinib (eg, CYP2C19 or 
CYP3A4 moderate/strong inhibitors/inducers), unless considered clinically indicated.
Strong or moderate inducers of CYP3A4 are not allowed at any time during the study. 
Concomitant use of strong or moderate inhibitors of CYP3A4 and CYP2C19 should be 
avoided until after the PK assessment on Cycle 2, Day 1. During the remainder of the study, if 
concomitant use of selumetinib with strong or moderate CYP3A4 and CYP2C19 inhibitors is 
not avoidable, then the selumetinib dose should be reduced by 20% as shown as an example 
for the granule formulation in Table I23 (note that the table uses the initial proposed dose for 
the selumetinib granule formulation; since the dose may be adjusted based on emerging safety, 
tolerability and PK data, the table may not include all scenarios). An example table for capsule 
dose reduction is shown in Table I24. The dose should be reduced for the duration of 
concomitant therapy with the strong or moderate CYP3A4 and CYP2C19 inhibitor and for 
5 half-lives afterwards. After the washout of the inhibitor is complete, the selumetinib dose 
can be re-escalated. The participant should be monitored closely for potential toxicities. If a 
participant has had a dose reduction, or the granule dose is not included in the table, 
Investigators may contact the AstraZeneca Medical Monitor for advice.
In vitro selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on 
the PK of concomitantly administered substrates of OAT3 (eg, methotrexate or furosemide) 
cannot be excluded and they should be given with caution.

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Table I23
Recommended Granule Dosage of Selumetinib for Co-administration 
with Strong or Moderate CYP3A4 and CYP2C19 Inhibitors based on 
the Initial Proposed Granule Dosing Scheme
Selumetinib dose 
(mg) bid starting 
dose a, b without 
CYP3A4 and 
CYP2C19 
inhibitors
Recommended granule dosage of 
selumetinib (mg) for co-administration 
with strong or moderate CYP3A4 and 
CYP2C19 inhibitors (20% reduction) c
Selumetinib granule dosage (mg) 
reduction for co-administration with 
strong or moderate CYP3A4 and 
CYP2C19 inhibitorsd
AM
PM
AM
PM
a.
Actual dose in mg administered every 12 hours to achieve exposure approximately 
to capsule in 
SPRINT; target median AUC =
 ng/mL at selumetinib dose 
mg/m2 BSA. 
b.
Sprinkle capsule dose strengths are and
 mg, it is recommended that a single sprinkle capsule strength 
is used to achieve a dose level where possible, to avoid dosing error. 
c.
If the current dosage is up to 
 mg/m2 bid, reduce to
 mg/m2 bid.
d.
If the current dosage is up to 
 mg/m2 bid, reduce to 
 mg/m2 bid.
AUC, area under the concentration time curve; bid, twice daily; BSA, body surface area; CYP, cytochrome P450.
Table I24
Recommended Capsule Dosage of Selumetinib for Co-administration 
with Strong or Moderate CYP3A4 and CYP2C19 Inhibitors
BSA (m2)
Recommended capsule dosage of 
selumetinib (mg) for co-administration 
with strong or moderate CYP3A4 and 
CYP2C19 inhibitors (20% reduction) a
Selumetinib capsule dosage (mg) 
reduction for co-administration with 
strong or moderate CYP3A4 and 
CYP2C19 inhibitors b
AM
PM
AM
PM
1.10 – 1.29
25
25
25
10
1.30 – 1.49
30
25
25
20
1.50 – 1.69
35
30
25
25
1.70 – 1.89
35
35
30
25
≥ 1.90
40
40
30
30
a.
If the current dosage is up to 25 mg/m2 bid, reduce to 20 mg/m2 bid.
b.
If the current dosage is up to 20 mg/m2 bid, reduce to 15 mg/m2 bid.
bid, twice daily; BSA, body surface area
CCI
CCI
CCI
CCI
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Changes to, or addition of medications detailed in Table I25 and Table I26 should be avoided, 
unless clinically indicated. The lists in Table I25 and Table I26 are not intended to be 
exhaustive, and a similar restriction will apply to other agents that are known to affect 
CYP2C19, or CYP3A4 activity. Appropriate medical judgment is required. Please contact 
AstraZeneca with any queries.
Table I25
Inhibitors of CYP2C19 or CYP3A4 that AstraZeneca Recommends not 
to be Combined with Selumetinib
CYP2C19
CYP3A4
Strong
Strong
Fluconazole
Indinavir
Fluvoxamine
Nelfinavir
Fluoxetine
Ritonavir
Ticlopidine
Saquinavir
Moderate
Cobicistat
(S)-omeprazole (esomeprazole) high dose 80 mg BD a
Telapravir
Stiripentol
Itraconazole
Voriconazole
Ketoconazole
Triclabendazole
Voriconazole
Cannabidiol b
Troleandomycin
Fedratinib
Mifepristone
Omeprazole
Clarithromycin
Efavirenz
Lonafarnib
Moclobemide
Posaconazole
Grapefruit juice
Conivaptan
Tucatinib
Ceritinib
Nelfinavir
Ribociclib
Idelalisib
Moderate
Erythromycin
Fluconazole
Atazanavir
Duvelisib
Diltiazem

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CYP2C19
CYP3A4
Dronedarone
Crizotinib
Fedratinib
Letermovir
Aprepitant
Lefamulin
Imatinib
Verapamil
Netupitant
Nilotinib
Tofisopam
Berotralstat
Ciprofloxacin
Voxelotor
Isavuconazole
Cimetidine
a.
There is literature evidence for esomeprazole causing weak CYP2C19 inhibition at 20 mg QD and moderate 
CYP2C19 inhibition at 80 mg QD, between this (eg, 20 mg BD) it is not confirmed at what dose 
esomeprazole changes from a weak to moderate inhibitor, therefore dose levels > 20 mg QD should be 
avoided with selumetinib.
b.
There is literature evidence for cannabidiol causing moderate CYP2C19 inhibition at doses of 750 mg bid 
for 7 days. There are no data at what dose cannabidiol becomes a moderate inhibitor, or if lower doses of 
cannabidiol cause CYP2C19 inhibition.
BD, twice daily; CYP, cytochrome P450; QD, once daily.
Table I26
Inducers of CYP3A4 that AstraZeneca Recommends not to be 
Combined with Selumetinib
CYP3A4 Strong
CYP3A4 Moderate
Rifampin
Efavirenz
Mitotane
Dabrafenib
Rifapentine
Cenobamate
Apalutamide
Bosentan
Phenytoin
Rifabutin
Carbamazepine
Lorlatinib
Enzalutamide
Nafcillin
Ivosidenib
Phenobarbital
St John's wort
Modafinil
Lumacaftor
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CYP3A4 Strong
CYP3A4 Moderate
Etravirine
Elagolix
Sotorasib
Telotristat ethyl
Nevirapine
CYP, cytochrome P450.

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Appendix J
Clinical Outcome Assessments
J 1
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J 2
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J 3
J 4
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J 5
 
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J 6
Palatability Scale
Study Medication Palatability Assessment
Observer Assessment for Children
Instructions to carers/parents – Immediately after administration of the selumetinib granule 
formulation, capture the child’s assessment of the taste of the medication.
1
Did your child take their study medication this [morning/evening]?
o
Yes (go to Question 3)
o
No (go to Question 2)
2
What was the reason for missing the dose?
(a) Study doctor/nurse told me to skip the dose (no further questions to be answered).
(b) I forgot to give my child the dose (no further questions to be answered).
(c)
My child did not want to take the dose (go straight to question 4).
(d)
My child could not swallow the study medication (go straight to question 4).
(e) Other (go straight to question 3).
3
Choose the response that best matches a description of what you observe of the child’s 
willingness to swallow the study medication.

Willingness to Swallow
o
Swallowed without problem 
o
Some resistance but did swallow
o
Spit out some/all of medication
o
Vomited up medication
4
Was any behaviour observed when the study medication was given to this child that 
would be indicative of a negative response to the palatability of the study medication? 
Palatability is the overall acceptance of the selumetinib granule medicine taken using soft 
food (as per the Handling Instructions) including taste, flavour, smell, amount of soft food 
used to take the medicine and texture.
o
Yes
o
No
If answered Yes, please answer the following questions:
(a) Did the child turn their head to reject intake of the medication?
o
Yes
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(b) Did the child twist their face or mouth in an expression of displeasure?
o
Yes
o
No
(c) Did the child display any other negative behaviour?
o
Yes
o
No
Handling and Dosing 
1
Were you able to prepare and dose the granules according to the Handling Instructions?

Yes 

No (go to Question 2)
2
If no, please indicate which area/s you had difficulty in following? 
(a) Difficulty identifying a suitable soft food.
(b) Identifying which sprinkle capsules are required for the dose. 
(c) Opening of sprinkle capsule.
(d) Pouring the granules onto a spoon.
(e) Pouring the granules into a dosing cup. 
(f) Adding soft food to the granules. 
(g) Mixing the soft food with the granules. 
(h) Giving the granules from a spoon.
(i)
Giving the granules from a dosing cup.
(j)
When using a dosing cup, adding further soft food to ensure the whole dose was 
taken. 
(k) Giving the whole dose within 30 minutes.
(l)
Other.

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Appendix K
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the AstraZeneca Medical Monitor.
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 8. Local and regional regulations and/or guidelines regarding reconsent 
of study participants should be checked and followed. Reconsent may be verbal if allowed by 
local and regional guidelines (note, in the case of verbal reconsent the ICF should be signed at 
the participant’s next contact with the study site). Visiting the study sites for the sole purpose 
of obtaining reconsent should be avoided.
Rescreening of Participants To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
Astra Zeneca Medical Monitor. 
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Section 5.4 the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to re-screen a participant. The procedures 
detailed in Table 2 must be undertaken to confirm eligibility using the same randomisation 
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Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the participants home/or other 
remote location as per local Standard Operating Procedures, applicable.
Supplies will be provided for a safe and efficient visit. The qualified HCP will be expected to 
collect information per the CSP. 
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
Home Delivery of Study Drug by a Designated Courier
If a site visit is not possible, selumetinib may be delivered to the participant's home by a 
designated courier if feasible. The option of home delivery ensures a participant’s safety in 
cases of a pandemic where participants may be at increased risk by travelling to the site/clinic. 
This will also minimise interruption of selumetinib administration during other study 
disruptions, eg, site closures due to natural disaster.
COVID-19 Vaccination
Investigators should follow their local prescribing information and policies when considering 
if vaccination against COVID-19 is appropriate for their patients participating in an 
AstraZeneca clinical trial.
Please consider the following if you are considering vaccinating your patient against 
COVID-19:
For a specific vaccine, consider the potential impact of its relevant prescribing information 
(i.e., Indications, Contraindications, Warnings and Precautions, Adverse Reactions) on its use 
in the study population.

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For patients with flexibility as to when to be enrolled in an Astra-Zeneca-sponsored study, 
vaccination prior to first dose of the trial investigational product(s) may be advisable.
Please contact the individual COVID-19 vaccine manufacturer if you have any questions 
concerning their product.
To better assess the overall impact of COVID-19 vaccination on a particular study and study 
population, ensure that both the COVID-19 vaccination details (including brand name and 
manufacturer) is captured in the eCRF as concomitant medication, and adverse reactions are 
reported.

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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
ADR
Adverse drug reaction
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
API
Active pharmaceutical ingredient
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve 
AUC0-6
Area under the concentration-time curve from time zero to 6 hours
AUC0-12
Area under the concentration-time curve from time zero to 12 hours
AUC0-24
Area under the concentration-time curve from time zero to 24 hours
AUClast
Area under the concentration-time curve from time zero to the last measurable 
concentration
B
Blood
bid
Twice daily
BNP
Brain natriuretic protein
BP
Blood pressure
BSA
Body surface area
C
Cycle
CFR
Code of Federal Regulations
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine kinase
CK-MB
Creatine kinase-myocardial band
CK-MM
Creatine kinase-muscle
CLss/F 
Apparent total clearance of the drug from plasma at steady state
CL/F 
Apparent total clearance of the drug from plasma
Cmax
Maximum peak plasma concentration
COA
Clinical Outcome Assessment
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CR
Complete response
CRO
Contract research organisation
CSP
Clinical study protocol
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Abbreviation or special 
term
Explanation
CSR
Central serous retinopathy
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trials Information System
CV
Coefficient of variation
CYP
Cytochrome P450
D
Day
 
DES
Data entry site
DCO
Data cut-off
DILI
Drug-induced liver injury
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EoT
End of Treatment
ePRO
Electronic patient-reported outcomes
ERK
Extracellular signal-regulated kinase
EU
European Union
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GTPase
Guanosine 5'-triphosphatase
Hb
Haemoglobin
HCP
Health Care Professional
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
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Abbreviation or special 
term
Explanation
HLT
High level term
IATA
International airline transportation association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICR
Independent central review
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International normalised ratio
International 
co-ordinating Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator coordinating the Investigators and/or activities 
internationally.
IOP
Intraocular pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
KM
Kaplan-Meier
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LVEF
Left ventricular ejection fraction
LVSD
Left ventricular systolic dysfunction
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities;
MEK
Mitogen activated protein kinase
MEKi
Mitogen activated protein kinase inhibitor
Min
Minimum
MPNST
Malignant peripheral nerve sheath tumours
MRI
Magnetic resonance imaging
n
Number
NC
Not calculated
NCA
Non-compartmental analysis
NCI
National Cancer Institute
NEC
Not elsewhere classified
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Abbreviation or special 
term
Explanation
NF1
Neurofibromatosis type 1
NIH
National Institutes of Health
NIMP
Non-investigational medicinal product
OAT3
Organic ion transporter 3
ORR
Objective response rate
P
Plasma
P-A
Posterior-anterior
PBMC
Peripheral blood mononuclear cells
PBPK
Physiologically based pharmacokinetics
PD
Progressive disease
pERK
Phosphorylated extracellular signal-regulated kinase
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)
PN
Plexiform neurofibroma
POB
Pediatric Oncology Branch
PR
Partial response
PRO
Patient-Reported Outcomes
PT
Preferred term
QTcB
QT interval corrected by Bazett’s method
QTcF
QT interval corrected by Fridericia’s method
Rac
Relative accumulation ratio
REiNS
Response Evaluation in Neurofibromatosis and Schwannomatosis
RNA
Ribonucleic acid
RPED
Retinal Pigment Endothelial Detachment
RT-PCR
Reverse transcription polymerase chain reaction
RTSM
Randomisation and Trial Supply Management
RVO
Retinal vein occlusion
S
Serum
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SMQ
Standardised MedDRA query
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Abbreviation or special 
term
Explanation
SoA
Schedule of Activities
SoC
Standard of care
SRC
Safety Review Committee
SUSAR
Suspected unexpected serious adverse reaction
TBL
Total bilirubin
t½λz
Elimination half life
tlast
Time to last measurable concentration
tmax
Time to maximum concentration
TPV 
Third Party Vendor
U 
Urine
ULN
Upper limit of normal
US
United States
V
Visit
VMI
Visual-Motor Integration
VO2
Maximal oxygen uptake
Vss/F
Apparent volume of distribution at steady state after non-intravenous 
administration 
Vz/F
Apparent volume of distribution after non-intravenous administration
W
Week
WBC
White blood cell
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Appendix M Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 3.0 (14 February 2023)
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union and in the EU Clinical Trial Regulation Article 2, 2 (13) as it neither 
significantly impacts the safety or physical/mental integrity of participants nor the scientific 
value of the study.
Overall Rationale for the Amendment:
The main purpose of the amendment is to clarify the requirement that the SRC will evaluate 
data during the dose finding phase after the first cycle of dosing: i) in '3 (maximum 4) 
evaluable participants' instead of 'the first 3 evaluable participants', and ii) that if a patient is 
classed as non-evaluable, additional patients will be dosed to ensure there is a minimum of 3 
evaluable participants. Clarifications have been made and other typographical errors have 
been corrected.
Summary of Non-substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Overall Design,  
6.1.2.2
Definition of 
an Evaluable 
Participant for the Dose 
finding Phase , 9.2
Sample Size 
Determination
Change to definition of evaluable patient (for 
both sample size and SRC)
Clarification to existing CSP 
language
Section 1.3, Schedule 
of Activities (Table 2)
Foot note z added “Consent can be performed 
from Day -42. All screening assessments must 
be performed within 28 days prior to dosing.”
To provide flexibility for 
consenting process
Figure 2 Dose finding 
phase
Updated flow diagram with “3 evaluable 
participants…” instead of ‘Recruit 3 
participants’ & “continue dosing into 
cohort…” instead of ‘continue recruitment 
into cohort…’
To align with the amended 
wording in Section 6.1.2 (Dose 
finding phase of the CSP.
Overall design , 
Section 4.1.2 Overall 
design 
Corrected text from 3 participants to dosing in 
3 evaluable participants in Cohort 1
To align with the requirement in 
section 6.1.2 (Dose finding phase) 
of the CSP that data from 3 
evaluable participants is required

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Section Number and 
Name
Description of Change
Brief Rationale
Section 5.4 Screen 
Failure
Clarification provided and text revised
To align with amended wording
Section 6.1.2 Dose 
Finding Process
Clarification provided to indicate that SRC 
will occur after 3 evaluable participants 
(maximum 4) instead of 3 evaluable 
participants. Clarification that if a patient is 
classed as non-evaluable, additional 
participants will be dosed to ensure there is a 
minimum of 3 evaluable participants. 
Clarified that whilst the SRC convenes 
‘dosing’ of additional participants will be 
paused instead of ‘recruitment’.
To clarify that data from 3 
evaluable patients is needed for 
the SRC review, and that data 
from a maximum of 4 evaluable 
participants may be available
Section 6.3 Measures 
to Minimise Bias: 
Randomisation and 
Blinding
Text added “Informed consent may be signed 
within 42 days of dosing window if it is more 
convenient for the site and families  .”
To align with the amended 
wording in Section 1.3, Schedule 
of Activities (Table 2)
Table 7 Initial 
Proposed Granule 
Formulation Dose 
Schema for 
Selumetinib
Rectified typo error for Dose level 
Clarification
Appendix H , Table 
H25 Inhibitors of 
CYP2C19 or CYP3A4 
that AstraZeneca 
Recommends not to be 
Combined with 
Selumetinib
Typo corrected to mention footnote “b” for 
Cannabidiol
Clarification
Amendment 2.0 (Version 3.0): (30 November 2022)
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union and in the EU Clinical Trial Regulation Article 2, 2 (13) as it neither 
significantly impacts the safety or physical/mental integrity of participants nor the scientific 
value of the study.
Overall Rationale for the Amendment:
The main purpose of the amendment is to include a new exploratory endpoint for biomarker 
analysis of residual PK or PD samples. The synopsis has been updated in line with changes to 
the protocol. Clarifications have been made and other typographical errors have been 

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corrected.
Summary of Non-substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, 
Section 3 Objectives 
and Endpoints
Inclusion of new exploratory objective.
To enable biomarker 
analysis of residual PK or 
PD samples
Section 1.1 Synopsis, 
Section 4.1.2 Overall 
Design, Section 6.7
Continued Access to 
Study Intervention 
after the End of the 
Study
Additional text added for post-trial access to 
selumetinib.
Update of AstraZeneca 
standard text
Section 1.3 Schedule of 
Activities, Table 2, 
footnote c
Text revised to clarify that an EoT visit will be 
performed for participants who permanently 
discontinue study intervention instead of 
selumetinib treatment.
Clarification
Section 1.3 Schedule of 
Activities, Table 2, 
footnote v
Removal of text ‘for an individual at least 
5 samples during 8-hour time period post first 
dose’.
Clarification
Section 4.4 End of 
Study Definition
New AstraZeneca standard text has been added to 
define the end of study as per EU and FDA 
regulatory requirements. The definition of study 
completion for individual participants has been 
added.
To provide guidance
Section 5.2 Exclusion 
Criteria (criterion 9)
Clarified that participants with known glaucoma 
that is clinically pain-free, has no clinically 
meaningful vision and has increased IOP may be 
permitted.
Participants with any other significant abnormality 
on ophthalmic examination should be reviewed for 
potential eligibility.
Clarification based on UK 
health authority feedback
Section 5.3.1 Meals 
and Dietary 
Restrictions
Update of list for fruit and juices to avoid. 
Added information to 
AstraZeneca standard text
Section 6.1.2.1
Pharmacokinetics and 
Safety/Tolerability 
Acceptability Criteria 
for the Dose finding 
Phase
Clarification on how the dose schema will be 
adjusted, and when it will not need to be adjusted. 
An exposure change 
(as measured by AUC0-12) 
less than 30% will not 
impact the safety or efficacy 
of selumetinib in paediatric 
participants

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Section Number and 
Name
Description of Change
Brief Rationale
Section 6.1.2.2
Definition of an 
Evaluable Participant 
for the Dose-finding 
Phase
New text added to clarify the definition of an 
evaluable participant for safety in the dose-finding 
phase.
To avoid confusion with 
regards to the definition of 
an evaluable participant for 
the dose-finding phase
Section 8.4.11
Medication Error, Drug 
Abuse, and Drug 
Misuse
New subsections added to provide additional 
information on medication error, drug abuse, and 
drug misuse.
Update of AstraZeneca 
standard text
Section 8.6 Human 
Biological Samples
The maximum storage time of biological samples 
has been updated to a maximum of 15 years from 
the date of the issue of the clinical study report in 
line with consent and local requirements.
Updated information
Section 8.7.1
Collection of 
Mandatory Samples for
Biomarker Analysis
Text amended to clarify there is no additional 
biomarker sample collection in this study.
To enable biomarker 
analysis of residual PK or 
PD samples
Section 8.7.2 Other 
Study-related 
Biomarker research
New section of text included.
New information added to 
enable biomarker analysis of 
residual PK or PD samples
Section 9.4.5 Other 
Analyses
Inclusion of new text for biomarker exploratory 
analyses.
New information added to 
enable biomarker analysis of 
residual PK or PD samples
Appendix A 1
Regulatory and Ethical 
Considerations
Update of AstraZeneca standard text to include 
detail of guidance to be followed including the 
Declaration of Helsinki, 21 CFR 312.120, ICH 
guidelines, the IRB/IEC, European Regulation 
536/2014 for clinical studies (if applicable), 
European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other 
applicable local regulations.
Update of AstraZeneca 
standard text
Appendix A 1
Regulatory and Ethical 
Considerations
New subsection added on ‘Regulatory Reporting 
Requirements for Serious Breaches’.
Update of AstraZeneca 
standard text
Appendix A 7 Data 
Quality Assurance
Bullet point added to confirm that AstraZeneca or 
designee is responsible for medical oversight 
throughout the conduct of the study.
Update of AstraZeneca 
standard text
Appendix B 4
Medication Error
A wrong dose (error greater than ± 10%) has been 
added as an example of drug not administered as 
indicated. New text on drug abuse and misuse has 
been added.
Update of AstraZeneca 
standard text

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Section Number and 
Name
Description of Change
Brief Rationale
Appendix I Guidance 
Regarding Potential 
Interactions with 
Concomitant 
Medications
Footnote added to clarify that there is literature 
evidence for cannabidiol causing moderate 
CYP2C19 inhibition at doses of 750 mg bid for 
7 days. There are no data at what dose cannabidiol 
becomes a moderate inhibitor, or if lower doses of 
cannabidiol cause CYP2C19 inhibition.
Clarification
Global
Minor editorial changes to wording and formatting.
To aid readability
AUC0-12, area under the concentration-time curve from time zero to 12 hours; CFR, Code of Federal 
Regulations; EoT, End of Treatment; EU, European Union; FDA, Food and Drug Administration; ICH, 
International Conference on Harmonisation; IEC, Independent Ethics Committee; IRB, Institutional Review 
Board; n, number: PK, pharmacokinetics. 
Amendment 1.0 (Version 2.0): (18 March 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The main purpose of the amendment is to add a new cohort of participants in Japan in order to 
generate PK and safety data from Japanese patients enrolled in Japan, add a new 
 
 exploratory endpoint, align to the updated IB, and to respond to Health Authority 
feedback. The synopsis has been updated in line with changes to the protocol. Clarifications 
have been made and other typographical errors have been corrected.
Changes are grouped according to whether they are Substantial or Non-Substantial.
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Summary of Substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Synopsis, Section 1.2
Schema, Section 2.2
Background, 
Section 4.1.2 Overall 
Design, Section 0
Scientific Rationale for 
Study Design, 
Section 6.1.2
Dose-finding Phase, 
Section 9.2 Sample 
Size Determination, 
Section 9.3 Populations 
for Analyses, Section 
9.4.1 General 
Considerations
Amended to include information relating to the 
addition of participants in Japan (Japan Cohort), 
including background information, number of 
planned participants in the cohort, clarification that 
PK data for the Japan Cohort will be summarised 
separately to the PK data for the Global Cohorts, 
clarification about the 3 analysis time points in 
relation to the Global and Japan Cohorts and 
clarification that the Japan Cohort will not be 
included in the dose-finding phase.
In order to generate PK and 
safety data from Japanese 
participants enrolled in 
Japan
Synopsis, Section 1.3
Schedule of Activities, 
Table 2, Section 6.1.1
Investigational 
Product, Section 
8.6.1.1 Collection of 
Samples, Table 15
New column added to Table 2 to show what 
assessments are to be made on Day 7 after 
transition of participants to the capsule formulation.
Addition of text to state that upon transition of 
participants from the granule formulation to the 
capsule formulation, PK sampling should be 
performed on Day 7 (range Day 4 to 14) and 
associated sampling timepoints.
Based on Health Authority 
feedback to include 
intensive PK sampling after 
transition of participants 
from granule to capsule 
formulation
Section 5.2 Exclusion 
Criteria, exclusion 
criterion 5, Section 
8.3.4
Electrocardiograms
QTcB changed to QTcF.
“Corrected QT” changed to QTcF and clarification 
added that if participants were enrolled using QTcB 
at screening (i.e., prior to this amendment) both 
QTcB and QTcF are to be collected at all 
timepoints throughout the study.
Based on Health Authority 
feedback
PK, pharmacokinetic; QTcB, QT interval corrected by Bazett’s method; QTcF, QT interval corrected by 
Fridericia’s method.
Summary of Non-substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Synopsis, Section 1.2
Schema, Section 4.1.2
Overall Design
Text amended to state that enrolment into the 
Global Cohorts will be stratified by age group; 
previously the protocol incorrectly implied that 
enrolment into the initial dose-finding phase was 
stratified by age group. 
To correct an error

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Section Number and 
Name
Description of Change
Brief Rationale
Synopsis, Section 2.1
Study Rationale
Text added to the rationale to make it clear that the 
relative bioavailability of selumetinib capsules to 
granules has already been investigated in adults 
therefore does not need to be repeated in paediatric 
participants. 
For clarification
Synopsis, Section 2.1
Study Rationale, 
Section 9.4.2.1 Primary 
and Secondary 
Endpoints
Text added to clarify that at the final sample size 
for the recommended dose schema in the Global 
Cohorts the AUC0-12 geometric mean and 
% CI 
will be determined for each age group and overall. 
Also clarified that exposure to selumetinib across 
the age groups in the SPRINKLE study will be 
considered comparable with exposure in the 
SPRINT study if the 
% CI falls within 
 
% of the geometric mean AUC0-12 observed in 
SPRINT.
For clarification
Synopsis, Section 3
Objectives and 
Endpoints, Table 5, 
Section 8.6.1.1, 
Collection of Samples
A new exploratory objective to determine the PK of 
selumetinib and N-desmethyl selumetinib after 
administration of the selumetinib capsule 
formulation was added.
Based on Health Authority 
feedback
Synopsis, Section 3
Objectives and 
Endpoints, Table 5, 
Section 9.4.2.2
Secondary Endpoint(s)
PK parameters updated to align with AstraZeneca 
standards.
In order to align with 
previously reported data
Synopsis, 
Section 6.1.2.1
Pharmacokinetics and 
Safety/Tolerability 
Acceptability Criteria 
for the Dose finding 
Phase
In the primary PK analysis text, “
 percentile” 
was changed to “
 percentile”.
Geometric mean was changed to median as this was 
the parameter used to set these criteria.
To correct terminology
Synopsis, Schedule of 
Activities Table 2, 
Section 3 Objectives 
and Endpoints Table 5, 
Section 8.3.10.1
Neurodevelopment 
Tests
Amendment to clarify that the 
 
is derived from the 
 
, that both the 
 
 will be performed, and that only the 
 test is required 
 
.
For clarification
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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities, Table 2
Addition of dispensing and return of 
medication/compliance checks at Cycle 19.
Addition of row to indicate daily drug diaries are to 
be completed twice daily from Cycle 1 Day 1 to 
Day 7 after transition to capsule formulation.
Addition of dispense/return ePRO device/review 
ePROs check at Day 7 after transition to capsule 
formulation.
Addition of review daily drug diary check at Day 7 
after transition to capsule formulation.
For clarification
Section 1.3 Schedule of 
Activities, Table 2
The assessment of disease characteristics at 
screening (including documenting location of the 
target and non-target PN [if applicable], any 
PN-related symptoms and results of any previous 
genetic testing for NF1) was added.
To enable collection of data 
for any previous genetic 
testing for NF1
Section 1.3 Schedule of 
Activities, Table 2
The need for PN assessments using volumetric MRI 
at the end of treatment was replaced by instruction 
to follow standard of care.
To reduce the participant 
burden of multiple MRIs in 
a close period of time
Synopsis, Section 3
Objectives and 
Endpoints, Table 5, 
Section 9.4.2.2
Secondary Endpoint(s)
A new exploratory objective to complete pooled 
 and exposure-response analyses for 
safety, biomarkers, and efficacy was added.
Information added regarding 
 
 analyses; they will be described in the 
modelling analysis plan and reported separately 
from the main Clinical Study Report.
Based on Health Authority 
feedback
Section 5.2 Exclusion 
Criteria
“Bilirubin” amended to “Total bilirubin”
To correct an inconsistency
Section 6.5
Concomitant Therapy, 
Appendix I Guidance 
Regarding Potential 
Interactions with 
Concomitant 
Medications
Addition of text to state that selumetinib is an 
inhibitor of OAT3 and as such substrates of OAT3 
should be given with caution.
To align to the updated IB, 
per EMA guidance
Section 8.6.1.2
Determination of Drug 
Concentration
Covance replaced by Labcorp as the assay 
laboratory
Update to assay laboratory
Appendix I Guidance 
Regarding Potential 
Interactions with 
Concomitant 
Medications
Updated Table I25 and Table I26 to include more 
concomitant medications.
To make the list of 
concomitant medications 
with potential interactions 
more comprehensive
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EMA, European Medicines Agency; IB, Investigator’s Brochure; MRI, magnetic resonance imaging; 
NF1, neurofibromatosis type 1; OAT3, organic ion transporter 3; PD, pharmacodynamic; PK, pharmacokinetic; 
PN, plexiform neurofibroma.

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11
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