A Phase III, Multicentre, International Study With a Parallel, Randomised, Double-blind, Placebo-controlled, 2 Arm Design to Assess the Efficacy and Safety of Selumetinib in Adult Participants With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas (KOMET)
Phase: PHASE3
Conditions: Neurofibromatosis 1, Plexiform Neurofibroma (PN)
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Selumetinib
Study Code
D134BC00001
Version
4.0 
Date
03 November  2023
EudraCT / EU CT 
Number
2020-005607-39 / 2023-
507336-20-00
A Phase III, Multicentre, International Study with a Parallel, 
Randomised, Double-blind, Placebo-controlled, 2 Arm Design to 
Assess the Efficacy and Safety of Selumetinib in Adult 
Participants with NF1 who have Symptomatic, Inoperable 
Plexiform Neurofibromas (KOMET).
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): 
IND 122851; EudraCT Number 2020-005607-39
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: D134BC00001
Amendment Number: 3

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Study Intervention: Selumetinib
Study Phase: Phase III
Short Title: Efficacy and Safety of Selumetinib in Adults with NF1 who have Symptomatic, 
Inoperable PN (KOMET)
Medical Monitor Name and Contact Information will be provided separately.
International co-ordinating investigator: 
, National Cancer Institute, Bethesda, MD, USA
National co-ordinating investigator:
, Hôpital Henri-Mondor, Paris, France
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Amendment 3.0 (Version 4.0): (XX month 2023) 
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 the removal of the fasting restriction after end of Cycle 
24, change to 1st key secondary endpoint estimand and include an additional key secondary 
endpoint.   
Summary of Changes
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1, Section 3, 
Section 9.4.2.1
Include intercurrent event strategy for primary 
estimand
In line with ICH E9 (R1) 
addendum 
Section 1.1, Section 3, 
Section 9.4.2.2.1
Update 1st key secondary estimand
To address regulatory 
feedback
Section 1.1, Section 3, 
Section 9.4.2.2.2
Upgrade secondary estimand PlexiQOL to an 
additional key secondary estimand of PlexiQOL
Update to company position 
that PlexiQOL intended for 
labelling purposes
Section 9.1, Section 9.5
Modify MTP to include 2nd key secondary estimand 
PlexiQOL and further information (scenarios) about 
the testing of key secondary endpoints
Update to company position 
that PlexiQOL intended for 
labelling purposes and to 
clarify the testing strategy 
within a key secondary 
endpoint.
Section 1.1, Section 3, 
Sections 9.4.2.3.7, 
9.4.2.3.9, 9.4.2.3.10, 
9.4.2.3.11, 9.4.2.3.13
Add estimate at each scheduled visits other than 
overall estimate over randomised treatment period 
for  the following  secondary endpoints: chronic 
target PN pain palliation, pain medication use, PII-
pNF pain interference total score, PROMIS 
Physical Function scores, PedsQL (NF1 module 
acute version 3.0 – adult report) skin sensations 
domain, EQ-5D-5L and EQ-VAS
To align with change to key 
secondary estimand to 
address regulatory feedback
Section 8.1.8
Remove endpoints description
Not applicable to this section
Appendix A7
Updated information about retention timelines of 
records and documents to 25 years after study 
archiving or as required by local regulations
Update required to comply 
with EU CTR and global 
company requirement

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1, 1.3; Table 
1: Schedule of 
Activities; Section 
5.2.1 and 6.1.1
Added the following wording to lift the fasting 
restriction from the end of C24: From the end of 
Cycle 24 (Cycle 25 Day 1) participants will not be 
required to continue to observe the fasting 
restriction, i.e participant can eat at any time point 
in relation to each medication intake (study 
intervention capsules). Refer to Section 5.2.1 for 
the definition of participant fed state.
To allow study drug to be 
administered in the fed state; 
modification follows an 
updated and more complete 
analysis of the food effect 
data for the program
Section 1.1 and Section 
4.1
Added detail about the food restriction lifting after 
C24
To align with removal of 
fasting restriction after C24; 
modification follows an 
updated and more complete 
analysis of the food effect 
data for the program
Section 1.1 and Section 
3 and section 9.3 
(Table 12)
Added an exploratory objective re efficacy in fed 
state after C24 and related new analysis set 
To align with removal of 
fasting restriction after C24; 
modification follows an 
updated and more complete 
analysis of the food effect 
data for the program
Section 8.1.1 and 8.1.8
Added text to clarify that if a participant taking part 
in the study had a target PN resection and remained 
in the study, MRI scans and PAINS-pNF data will 
continue to be collected.
Clarification
Global
Minor editorial changes to wording and formatting
To aid readability
bid, Twice daily; BSA, Body surface area; C1D1, Cycle 1 Day 1; CFR, Code of Federal Regulations; CTIS, 
Clinical Trials Information System; CYP, Cytochrome P450; EU, European Union; FDA, Food and Drug 
Administration; ICH, International Conference on Harmonisation; IEC, Independent Ethics Committee; IOP, 
Intraocular pressure; IRB, Institutional Review Board; IRT, Interactive Response Technology; NF1, 
Neurofibromatosis type 1; PN, Plexiform neurofibroma; PK, Pharmacokinetics; UK, United Kingdom.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 5
LIST OF FIGURES .............................................................................................................. 8
LIST OF TABLES ................................................................................................................ 8
1
PROTOCOL SUMMARY ................................................................................ 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 27
1.3
Schedule of Activities ....................................................................................... 27
2
INTRODUCTION............................................................................................ 36
2.1
Study Rationale ................................................................................................ 36
2.2
Background ...................................................................................................... 36
2.3
Benefit/Risk Assessment................................................................................... 38
2.3.1
Risk Assessment ............................................................................................... 38
2.3.2
Benefit Assessment........................................................................................... 41
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 41
3
OBJECTIVES AND ENDPOINTS................................................................... 41
4
STUDY DESIGN ............................................................................................. 50
4.1
Overall Design.................................................................................................. 50
4.2
Scientific Rationale for Study Design ............................................................... 52
4.2.1
Participant Input into Design............................................................................. 53
4.3
Justification for Dose........................................................................................ 53
4.4
End of Study Definition.................................................................................... 55
4.5
Study Conduct Mitigation during Study Disruptions due to Cases of Civil Crisis, 
Natural Disaster, or Public Health..................................................................... 56
5
STUDY POPULATION.................................................................................... 57
5.1
Inclusion Criteria .............................................................................................. 57
5.2
Exclusion Criteria ............................................................................................. 60
5.2.1
Meals and Dietary Restrictions ......................................................................... 63
5.2.2
Alcohol............................................................................................................. 64
5.2.3
Activity............................................................................................................. 64
5.3
Screen Failures ................................................................................................. 64
6
STUDY INTERVENTION ............................................................................... 65
6.1
Study Intervention(s) Administered................................................................... 65
6.1.1
Investigational Products.................................................................................... 65
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 67

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6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 67
6.4
Study Intervention Compliance......................................................................... 70
6.5
Concomitant Therapy........................................................................................ 71
6.6
Dose Modification ............................................................................................ 72
6.7
Intervention after the End of the Study.............................................................. 73
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 74
7.1
Discontinuation of Study Intervention............................................................... 74
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention............... 75
7.2
Participant Withdrawal from the Study.............................................................. 75
7.3
Lost to Follow-up ............................................................................................. 76
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 76
8.1
Efficacy Assessments........................................................................................ 77
8.1.1
Imaging of the Target PN.................................................................................. 77
8.1.2
Independent Central Review of Scans............................................................... 79
8.1.3
Objective Response Rate .................................................................................. 79
8.1.4
Progression Free Survival ................................................................................. 79
8.1.5
Duration of Response........................................................................................ 79
8.1.6
Time to Progression.......................................................................................... 80
8.1.7
Time to Response.............................................................................................. 80
8.1.8
Clinical Outcome Assessments.......................................................................... 80
8.1.8.1
PAINS-pNF ...................................................................................................... 81
8.1.8.2
PII-pNF ............................................................................................................ 81
8.1.8.3
Pain Medication Assessment Diary ................................................................... 82
8.1.8.4
PROMIS........................................................................................................... 82
8.1.8.5
PlexiQoL .......................................................................................................... 82
8.1.8.6
PedsQL (NF1 Module Acute Version 3.0 – Adult Report) Skin Sensations 
Domain............................................................................................................. 83
8.1.8.7
PGIC and PGIS................................................................................................. 83
8.1.8.8
EQ-5D-5L ........................................................................................................ 83
8.1.8.9
Administration of ePRO Questionnaires............................................................ 84
8.1.8.10
Qualitative Participant Interviews ..................................................................... 86
8.2
Safety Assessments........................................................................................... 86
8.2.1
Physical Examinations...................................................................................... 86
8.2.2
Height and Weight ............................................................................................ 87
8.2.3
Vital Signs ........................................................................................................ 87
8.2.4
Electrocardiograms ........................................................................................... 88
8.2.5
Echocardiogram/Cardiac MRI .......................................................................... 88
8.2.6
Clinical Safety Laboratory Assessments............................................................ 89
8.2.7
Ophthalmologic Examinations .......................................................................... 91
8.2.8
Other Safety Assessments ................................................................................. 91
8.2.8.1
ECOG Performance Status................................................................................ 91
8.3
Adverse Events and Serious Adverse Events..................................................... 92

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8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 92
8.3.2
Follow-up of AEs and SAEs ............................................................................. 92
8.3.3
Causality Collection.......................................................................................... 93
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 93
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 94
8.3.6
Hy’s Law.......................................................................................................... 94
8.3.7
Disease Progression.......................................................................................... 94
8.3.8
Disease Under Study......................................................................................... 95
8.3.9
Deaths .............................................................................................................. 95
8.3.10
Adverse Events of Special Interest.................................................................... 95
8.3.11
Safety Data to be Collected Following the Final DCO of the Study................... 96
8.3.12
Reporting of Serious Adverse Events ................................................................ 96
8.3.13
Pregnancy......................................................................................................... 97
8.3.13.1
Maternal Exposure............................................................................................ 97
8.3.13.2
Paternal Exposure............................................................................................. 98
8.3.14
Medication Error, Drug Abuse, and Drug Misuse.............................................. 98
8.3.14.1
Timelines.......................................................................................................... 98
8.3.14.2
Medication Error............................................................................................... 99
8.3.14.3
Drug Abuse....................................................................................................... 99
8.3.14.4
Drug Misuse ..................................................................................................... 99
8.3.15
Medical Device Deficiencies............................................................................. 99
8.4
Overdose .......................................................................................................... 99
8.5
Human Biological Samples............................................................................. 100
8.5.1
Pharmacokinetics............................................................................................ 100
8.5.1.1
Determination of Drug Concentration ............................................................. 101
8.5.2
Pharmacodynamics......................................................................................... 102
8.6
Human Biological Sample Biomarkers ........................................................... 102
8.6.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 102
8.6.2
Other Study-related Biomarker Research ........................................................ 102
8.7
Optional Genomics Initiative Sample.............................................................. 102
8.8
Medical Resource Utilisation and Health Economics ...................................... 102
9
STATISTICAL CONSIDERATIONS.............................................................. 103
9.1
Statistical Hypotheses..................................................................................... 103
9.2
Sample Size Determination............................................................................. 106
9.3
Populations for Analyses................................................................................. 107
9.4
Statistical Analyses ......................................................................................... 108
9.4.1
General Considerations................................................................................... 109
9.4.2
Efficacy .......................................................................................................... 109
9.4.2.1
Primary Endpoint............................................................................................ 109
9.4.2.2
Key Secondary Endpoints................................................................................111
9.4.2.3
Secondary Endpoints ...................................................................................... 115
9.4.2.4
Exploratory Endpoints .................................................................................... 123
9.4.3
Safety ............................................................................................................. 123
9.4.3.1
Adverse Events............................................................................................... 123

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9.4.3.2
Treatment emergent AEs................................................................................. 124
9.4.3.3
Vital Signs ...................................................................................................... 124
9.4.3.4
Laboratory Parameters.................................................................................... 124
9.4.3.5
Other Safety Endpoint(s) ................................................................................ 124
9.4.4
Other Analyses................................................................................................ 124
9.4.4.1
Pharmacokinetics............................................................................................ 124
9.4.4.2
Biomarker Analysis......................................................................................... 125
9.4.4.3
Optional Exploratory Genetic Sample............................................................. 125
9.5
Interim Analyses............................................................................................. 125
9.6
Data Monitoring Committee ........................................................................... 127
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 127
11
REFERENCES............................................................................................... 210
LIST OF FIGURES
Figure 1
Multiple Testing Procedure...................................................................... 26
Figure 2
Study Design ........................................................................................... 27
Figure 3
Multiple Testing Procedure.................................................................... 104
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 28
Table 2
Schedule of Telephone Assessments........................................................ 35
Table 3
Risk Assessment...................................................................................... 39
Table 4
Objectives and Endpoints......................................................................... 41
Table 5
Investigational Products........................................................................... 65
Table 6
Body Surface Area Dosing Guidelines..................................................... 66
Table 7
Dose Modification Procedure................................................................... 73
Table 8
Laboratory Safety Variables..................................................................... 90
Table 9
Adverse Events of Special Interest........................................................... 96
Table 10
Pharmacokinetic Sampling Schedule ..................................................... 101
Table 11 
Scenarios for the power of the second key secondary endpoint............... 107
Table 12
Populations for Analysis ........................................................................ 108
Table F12
Highly Effective Methods of Contraception (< 1% Failure Rate) ........... 153
Table H13
Treatment Recommendations for AE Paronychia a................................. 188
Table I14
Canadian Cardiovascular Society Grading of Angina Pectoris ............... 190
Table I15
New York Heart Association Classification ........................................... 190

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Table J16
Recommended Dosage of Selumetinib for Co-administration with Strong 
or Moderate CYP2C19 or CYP3A4 Inhibitors ....................................... 191
Table J17
Inhibitors of CYP2C19 or CYP3A4 that AstraZeneca Recommends not 
to be Combined with Selumetinib .......................................................... 192
Table J18
Inducers of CYP3A4 that AstraZeneca Recommends not to be 
Combined with Selumetinib................................................................... 194
Table J19
Restricted and Prohibited Medications/Therapies................................... 194
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 128
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 134
Appendix C
Handling of Human Biological Samples ................................................ 140
Appendix D
Optional Genomics Initiative Sample..................................................... 142
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 146
Appendix F
Contraception Requirements.................................................................. 151
Appendix G
Patient-reported Outcomes..................................................................... 154
Appendix H
Guidance for Management of Specific Adverse Events.......................... 181
Appendix I
Cardiovascular Grading ......................................................................... 190
Appendix J
Concomitant Medications ...................................................................... 191
Appendix K
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 196
Appendix L
Abbreviations ........................................................................................ 199
Appendix M
Protocol Amendment History................................................................. 203
Appendix N
Country Specific Requirements.............................................................. 209

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Objectives
Estimands descriptions/Endpoints
To demonstrate the effectiveness of selumetinib by 
assessment of DoR in participants with NF1 who 
have symptomatic, inoperable PN.
The duration of response will be defined as the 
time from the date of first documented response 
(which is subsequently confirmed) until date of 
documented progression by ICR per REiNS 
criteria or death due to any cause. The analysis 
will include all participants randomised to 
selumetinib with measurable target PN at 
baseline per ICR who received at least one dose 
of selumetinib and with a confirmed CR or 
confirmed PR prior to study intervention 
discontinuation. Duration of response will be 
derived using while on-treatment MRI 
volumetric assessments.
To demonstrate the effectiveness of selumetinib by 
assessment of PFS in participants with NF1 who 
have symptomatic, inoperable PN.
Progression free survival is defined as the time 
from the date of first selumetinib dose until date 
of progression by ICR per REiNS criteria or 
death (due to any cause). The analysis 
will include all participants randomised to 
selumetinib with measurable target PN at 
baseline per ICR who received at least one dose 
of selumetinib. Progression free survival will be 
derived using while on-treatment MRI 
volumetric assessments.
To demonstrate the effectiveness of selumetinib by 
assessment of TTP in participants with NF1 who 
have symptomatic, inoperable PN.
Time to progression is defined as the time from 
the date of first selumetinib dose until date of 
documented objective disease progression by 
ICR per REiNS criteria. The analysis will include 
all participants randomised to selumetinib with 
measurable target PN at baseline per ICR who 
received at least one dose of selumetinib. Time 
to progression will be derived using while 
on-treatment MRI volumetric assessments.

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Objectives
Estimands descriptions/Endpoints
To demonstrate the effectiveness of selumetinib by 
assessment of TTR in participants with NF1 who 
have symptomatic, inoperable PN.
Time to response is defined as the time from date 
of first selumetinib dose until the date of first 
documented objective response (which is 
subsequently confirmed), by ICR per REiNS 
criteria. The analysis will include all participants 
randomised to selumetinib with measurable 
target PN at baseline per ICR and who received 
at least one dose of selumetinib and with a 
confirmed CR or confirmed PR prior to 
selumetinib discontinuation. Data obtained from 
first dose up until progression, or the last 
evaluable assessment in the absence of 
progression, will be included in the assessment 
of TTR. Time to response will be derived using 
while on-treatment MRI volumetric assessments.
To demonstrate the effect of selumetinib relative to 
placebo by assessment of percentage change from 
baseline in target PN volume in participants with 
NF1 who have symptomatic, inoperable PN.
Difference in best percentage change from 
baseline in target PN volume by ICR per REiNS 
criteria between selumetinib and placebo during 
the randomised period. The analysis will include 
all participants randomised to study intervention 
with measurable target PN at baseline per ICR. 
The best percentage change from baseline in 
target PN volume will be derived using while 
on-treatment MRI volumetric assessments during 
the randomised period.
To compare the effect of selumetinib relative to 
placebo by assessment of chronic target PN pain 
palliation and time to chronic target PN pain 
palliation in participants with a PAINS-pNF chronic 
target PN pain score of ≥ 3 at baseline.
Chronic target PN pain palliation is defined as 
improvement of ≥ 2 in average cycle PAINS-
pNF chronic target PN pain intensity score and 
no increase in chronic PN pain medication 
compared to baseline for that cycle. Pain 
palliation will be assessed in participants with a 
PAINS-pNF chronic target PN pain score of ≥3 
at baseline.

Difference in proportion of participants with 
chronic target PN pain palliation between 
selumetinib and placebo at post-baseline cycles 
and overall over the randomised treatment period.

Time to chronic target PN pain palliation is 
defined as the time from the first dose of 
study drug until the cycle of chronic target 
PN pain palliation.

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Objectives
Estimands descriptions/Endpoints
To compare the effect of selumetinib relative to 
placebo by assessment of pain medication compared 
with baseline.
Difference in change from baseline in pain 
medication use (as reported using the eDiary) 
and as assessed by the investigator) between 
selumetinib and placebo at post-baseline cycles 
and overall over the randomised treatment 
period. 
To compare the effect of selumetinib relative to 
placebo by assessment of pain interference compared 
with baseline.
Difference in change from baseline in PII-pNF 
pain interference total score  between 
selumetinib and placebo at at post-baseline 
cycles and overall over the randomised treatment 
period. 
To compare the effect of selumetinib relative to 
placebo by assessment of physical functioning 
compared with baseline.
Difference in change from baseline in PROMIS 
Physical Function scores between selumetinib 
and placebo at post-baseline cycles and overall 
over the randomised treatment period.
To compare the effect of selumetinib relative to 
placebo by further assessment of HRQoL compared 
with baseline.
Difference in change from baseline in the Skin 
Sensations domain from the PedsQL (NF1 
module acute Version 3.0 – adult report) 
between selumetinib and placebo a at post-
baseline cycles and overall over the randomised 
treatment period.
To compare the effect of selumetinib relative to 
placebo by assessment of health status compared 
with baseline.
Difference in change from baseline in EQ-5D-5L 
between selumetinib and placebo at post-baseline 
cycles and overall over the randomised treatment 
period.
Difference in change from baseline in EQ-VAS 
between selumetinib and placebo at post-baseline 
cycles and overall over the randomised treatment 
period.
To evaluate the effect of selumetinib by assessment 
of physical functioning compared with baseline.
Change from baseline in PROMIS Physical 
Function items.
To evaluate the effect of selumetinib by assessment 
of HRQoL compared with baseline.
Change from baseline in PlexiQoL.
Change from baseline in the Skin Sensations 
domain from the PedsQL (NF1 module acute 
Version 3.0 – adult report).

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Objectives
Estimands descriptions/Endpoints
To evaluate the effect of selumetinib by assessment 
of health status compared with baseline.
Change from baseline in EQ-5D-5L 
(standardised measure of health status). Five 
dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Change 
from baseline in EQ-VAS.
To assess the PK of selumetinib.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 

Cmax, AUC(0-6), AUC(0-8), AUClast, 
CL/F, Vss/F, tmax, tlast derived after 
multiple dose administration.
•
Plasma concentrations and PK parameters of 
N desmethyl selumetinib including, but not 
limited to:

Cmax, AUC(0-6), AUC(0-8), AUClast, 
tmax , tlast derived after multiple dose 
administration.

MPAUC and MPCmax after multiple dose 
administration.
Population PK-pharmacodynamic analyses will 
be completed to investigate the selumetinib 
exposure-response relationship for safety and 
efficacy. The analyses will be reported separately 
from the Clinical Study Report.

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AE, adverse event; AUC(0-6), area under the concentration-time curve from time 0 to 6 hours; AUC(0-8), area 
under the concentration-time curve from time 0 to 8 hours; AUClast, area under the concentration-time curve 
from time 0 to time of last quantifiable concentration; BP, blood pressure; CL/F, apparent total body clearance of 
the drug from plasma after extravascular administration; Cmax, maximum observed concentration; CR, complete 
response; CTC, Common Terminology Criteria; DoR, duration of response; ECG, electrocardiogram; ECHO, 
echocardiogram; EQ-5D-5L, EuroQol 5-Dimension 5-level; EQ-VAS, EuroQol visual analogue scale; HRQoL, 
health related quality of life; ICR, independent central review; IOP, intraocular pressure; IP, investigational 
product; LVEF, Left ventricular ejection fraction; MEK, Mitogen activated protein kinase; MPAUC, Metabolite: 
parent ratio based on AUC; MPCmax, Metabolite:parent ratio based on Cmax; MRI, magnetic resonance 
imaging; NF1, Neurofibromatosis type 1; ORR, Objective response rate; PAINS-pNF, PAin INtensity Scale for 
Plexiform Neurofibromas; PedsQL, Paediatric Quality of Life Inventory; PFS, Progression free survival; 
PII-pNF, Pain interference index – plexiform neurofibroma; PK, pharmacokinetic(s); PlexiQoL, Plexiform 
Neurofibroma Quality of Life scale; PN, Plexiform neurofibroma(s); PR, partial response; 
PROMIS, Patient-Reported Outcomes Measurement Information System; REiNS, Response Evaluation in 
Neurofibromatosis and Schwannomatosis; tlast, time of last observed concentration; RNA, Ribonucleic acid; 
tmax, time to reach maximum observed concentration following drug administration; TTP, time to progression; 
TTR, time to response; Vss/F, volume of distribution (apparent) at steady state after extravenous administration.
Overall Design
This is a Phase III, multicentre, international study with a parallel, randomised, double-blind, 
placebo-controlled, 2 arm design to assess the efficacy and safety of selumetinib in adult 
participants with NF1 who have symptomatic, inoperable PN.
During screening, a single target PN will be selected by the investigator and is defined as the 
clinically most relevant PN, which has to be measurable by volumetric MRI analysis (ie, a PN 
of at least 3 cm measured in one dimension, which can be seen on at least 3 imaging slices, 
and has a reasonably well-defined contour). If there is a second PN that is also considered 
clinically relevant and is measurable, the investigator may select this as a non-target PN; only 
one non-target PN can be selected. 
As PN’s are often associated with multiple co-morbidities such as pain and motor dysfunction, 
these elements will be assessed using various PRO tools.
Pain, associated with the target PN, will be assessed using the PAINS-pNF, a modified 
NRS-11 pain scale for use in NF1-PN that measures the participant’s usual chronic tumour 
pain as well as sudden bursts of tumour pain that may occur, known as spikes of tumour pain. 
The average baseline chronic target PN pain intensity score will be used to stratify the 
participants into those who have a PAINS-pNF chronic target PN pain score of ≥ 3 and those 
with milder, intermittent or no chronic pain, a PAINS-pNF chronic target pain score of < 3.
Chronic PN pain and spike pain medication use will be assessed during the study and all 
participants should have stable chronic PN pain medication use at baseline, defined as no 
clinically significant changes to prescribed chronic PN pain medication within 28 days prior to 
study enrolment or planned at the time of study enrolment. All participants will be expected to 
complete PN pain intensity assessments using the e-Diary in the screening period. During this 

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time, participants must complete their pain diary for at least 4 days out of 7 days for at least 
2 weeks in order to determine the participant’s average baseline chronic target PN pain 
intensity score which is required for stratification.
Participants will be randomised 1:1 to receive selumetinib or placebo; randomisation will be 
stratified by average baseline chronic target PN pain score and geographical region. 
Participants on the placebo arm will be crossed over to selumetinib treatment after the end of 
Cycle 12. Crossover to selumetinib treatment during the randomised period may be permitted 
at an earlier timepoint for participants with documented progression on imaging, as 
determined by ICR, per REiNS criteria. Participants will be blinded to their treatment during 
the randomised period. Following crossover to selumetinib treatment, subsequent treatment 
will be open-label.
The interim analysis (DCO1) will occur after the 100th randomised participant has had the 
opportunity to complete their end of Cycle 16 assessment and the primary analysis (DCO2) 
will occur after the last participant dosed (the last participant receiving first dose) has had the 
opportunity to complete their end of Cycle 16 assessment. The primary analysis of ORR will 
be assessed at the end of Cycle 16 landmark in all randomised participants with measurable 
target PN at baseline per ICR. The summary measure of the 1st key secondary endpoint is the 
difference in the mean change from baseline in PAINS-pNF chronic target PN pain intensity 
score at Cycle 12 between selumetinib compared to placebo. This will be assessed in 
participants with a PAINS-pNF chronic target PN pain intensity score of ≥3 at baseline and at 
least one post-baseline average cycle PAINS-pNF chronic target PN pain intensity score. The 
summary measure of the 2nd key secondary endpoint is the difference in the mean change from 
baseline in PlexiQOL total score at Cycle 12 between selumetinib compared to placebo. This 
will be assessed in all randomized participants with a PlexiQOL total score at baseline and at 
least one post-baseline total score. The final analysis (Final DCO) will occur approximately 
24 cycles post last participant dosed to further characterise selumetinib efficacy and safety.  As 
each participant reaches the end of Cycle 24 (Cycle 25 Day 1), they will then be permitted to 
eat at any time point in relation to each selumetinib intake and considered in fed state. The 
data obtained in the fed state will be analysed in line with the main study analysis. Refer to 
Section 5.2.1 for the definition of participant fed state.
If the interim analysis DCO (DCO1) is due to take place within approximately 4 months of the 
primary analysis DCO (DCO2), then the interim analysis may not be performed and only the 
primary analysis will be performed.

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Disclosure Statement:
This is a Phase III, parallel, randomised, double-blind, placebo-controlled, 2 arm multicentre, 
international study assessing the efficacy and safety of selumetinib compared with placebo in 
adult participants with NF1 who have symptomatic, inoperable PN.
Participant Population:
The target population of interest in this study is adult participants with NF1 who have 
symptomatic, inoperable PN where: 

Symptomatic is defined as clinically significant symptoms caused by the PN, as judged 
by the investigator; symptoms may include, but are not limited to, pain, motor 
dysfunction and disfigurement.

Inoperable is defined as a PN that cannot be completely surgically removed without a risk 
of substantial morbidity (including significant bleeding or damage to nerves and/or 
surrounding vital structures) due to encasement of, or close proximity to, vital structures, 
invasiveness, or high vascularity of the PN; or unacceptable risk from the anaesthetic as 
assessed by the investigator.
Number of Participants:
It is estimated that approximately 212 participants with NF1 who have symptomatic, 
inoperable PN will be enrolled at approximately 46 sites across 13 countries to achieve 
approximately 145 participants randomised to study intervention. It should be noted that 
screening will continue until the required number of participants are randomised. If it is 
anticipated that 20% or more of participants (across blinded study intervention groups) 
withdraw prior to the end of Cycle 16, for reasons other than progression, then recruitment 
rates withstanding, enrolment will continue to randomise at least 50% of the total number of 
drop-out participants to ensure the primary endpoint is adequately powered.
Note: “Enrolled” means a participant’s 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 are not randomly assigned in the study, are 
considered “screen failures”, unless otherwise specified by the protocol. 
Intervention Groups and Duration:
Following a screening period lasting up to 28 days, eligible participants will be randomised in 
a 1:1 ratio to one of the following intervention groups:

Arm A: selumetinib 25 mg/m2 orally bid

Arm B: placebo orally bid

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Randomisation will be stratified by average baseline PAINS-pNF chronic target PN pain score 
and geographical region. The number of participants randomised will be capped at 
approximately 106 participants with an average baseline PAINS-pNF chronic target PN pain 
score ≥ 3 and approximately 40 participants with an average baseline PAINS-pNF chronic 
target PN pain score < 3.
Participants in the selumetinib group will receive 25 mg/m2 selumetinib as oral capsules bid 
until a selumetinib discontinuation criterion is met. Dosing will be based on BSA and capped 
at 50 mg bid when BSA is ≥ 1.9 m2.
Participants in the placebo group will receive placebo as oral capsules twice daily and will be 
crossed over to selumetinib treatment after the end of Cycle 12. 
The proposed duration for the study is approximately 24 months from last participant dosed to 
provide mature efficacy data as well as further safety and tolerability data. 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 and in 
the absence of discontinuation criteria.
Follow-up of Participants Post Discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
and will be followed up for safety assessments 30 days after their last dose of study 
intervention (ie, the safety follow-up visit).
See Section 6.7 for a description of assessments following study DCO.
Independent Data Monitoring Committee: 
Given that the randomised portion of the study is of limited duration, the participant 
population is not considered vulnerable and the safety profile of selumetinib is well 
established, an IDMC is not deemed to be necessary.

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Statistical Methods
Primary Estimand
The primary endpoint of ORR by end of Cycle 16 includes all randomised participants with 
measurable target PN at baseline as determined by ICR (Measurable PN FAS). The ORR is 
defined as the proportion 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 PR (defined as a target PN volume decrease ≥ 
20%, compared with baseline, confirmed by a consecutive scan within 3 to 6 months after the 
first response) by end of Cycle 16 as determined by ICR per REiNS criteria.  
Intercurrent events are addressed as follows:

Scans following randomised study intervention discontinuation will not be included in 
the analysis, assuming a while-on-treatment strategy to the intercurrent event of 
randomised study intervention discontinuation (including early crossover from placebo 
and progression) prior to end of cycle 16 due to any reason. 

Scans following the first 28 days of a prolonged study intervention interruption 
(defined as a study intervention interruption greater than or equal to 28 days) until 
study intervention has recommenced for at least 28 days will not be included in the 
analysis, assuming a while-on-treatment strategy to the intercurrent event of prolonged 
study intervention interruption.

Scans after target PN surgical resection will be included in the analysis assuming a 
treatment policy approach to the intercurrent event of target PN resection. 

Scans after subsequent NF1-PN treatment will not be included in the analysis 
assuming a while-on-treatment strategy to the intercurrent event of subsequent NF1-
PN treatment.
The primary endpoint ORR will be compared at the landmark end of Cycle 16 between 
selumetinib versus placebo using a Fisher’s exact test. ORR in each treatment group will be 
presented with corresponding two-sided exact 95% confidence interval (CI) based on the 
Clopper-Pearson method (Clopper and Pearson 1934). The risk difference and 95% CI based 
on the Miettinen-Nurminen (score) method (Miettinen and Nurminen 1985) will also be 
presented.
Key Secondary Estimands
PAINS-pNF chronic target PN pain intensity
The 1st key secondary estimand is the difference of the means in the change from baseline in 

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PAINS-pNF chronic target PN pain intensity score at Cycle 12 between selumetinib and 
placebo, amongst participants with a PAINS-pNF chronic target PN pain score ≥ 3 at baseline 
(Pain FAS) and at least one post-baseline average cycle PAINS-pNF chronic target PN pain 
intensity score. 
Intercurrent events are addressed as follows:

Changes to participants’ chronic PN pain medication will be included assuming the 
treatment policy strategy to the intercurrent event of changes in participant’s chronic 
PN pain medication.

PAINS-pNF scores following randomised study intervention discontinuation will not 
be collected and will be modelled through direct likelihood techniques assuming a 
hypothetical strategy to the intercurrent event of randomised study intervention 
discontinuation prior to end of cycle 12 due to any reason. 

PAINS-pNF scores after early crossover from placebo to selumetinib in participants 
with documented progression on imaging (as determined by ICR per REiNS criteria) 
will be set to missing assuming a while-on-treatment strategy to the intercurrent event 
of early crossover from placebo to selumetinib. 

PAINS-pNF scores after the first 28 days of a prolonged study intervention  
interruption until day prior to study intervention recommencement will be set to 
missing assuming a while-on-treatment strategy to the intercurrent event of prolonged 
study intervention interruption (defined as a study intervention interruption greater 
than or equal to 28 days).

PAINS-pNF scores after a target PN surgical resection will be included in the analysis 
assuming a treatment policy approach to the intercurrent event of target PN resection. 
The response variable for a cycle will be the average cycle PAINS-pNF chronic target PN pain 
score change from baseline defined as the average of the available daily PAINS-pNF chronic 
target PN pain scores for the 28 days up to and including the last day of the cycle minus the 
baseline chronic target PN pain score. The average cycle PAINS-pNF chronic target PN pain 
score will only be derived if the participant meets the criteria of having at least 4 daily pain 
scores out of 7 days for at least 3 nonoverlapping 7-day periods in the 28-day cycle. Baseline 
PAINS-pNF chronic target PN pain score is defined as the average of the available daily 
PAINS-pNF chronic target PN pain scores in the screening period (a minimum of 4 out of 7 
days for at least 2 weeks).
The difference in the mean change from baseline in PAINS-pNF chronic target PN pain score 
at Cycle 12 between selumetinib and placebo and 95% CI will be assessed by means of a 

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mixed model for repeated measures (MMRM) with treatment, cycle number and geographic 
region as categorical fixed effects, the baseline PAINS-pNF chronic target PN pain intensity 
score as a continuous covariate and treatment-by-cycle number and baseline PAINS-pNF 
score-by-cycle number interactions.  Parameters will be estimated with the restricted 
maximum likelihood (REML) approach and the Kenward-Roger approximation is used to 
estimate the degrees of freedom. An unstructured covariance matrix will be used to allow for 
unequal treatment variance and to model the correlation between different treatment 
measurements within the same subject. If the fit of the unstructured covariance structure fails 
to converge, the following covariance structures will be used in order until convergence is 
reached: toeplitz with heterogeneity, autoregressive with heterogeneity, toeplitz, 
autoregressive and compound symmetry. 
Missingness will be examined, and sensitivity analyses will be performed as appropriate. In 
addition, supplementary analyses for alternative estimands will be explored.
PlexiQOL
The 2nd key secondary estimand is the difference of the means in the change from baseline in 
PlexiQOL total score at Cycle 12 between selumetinib and placebo, amongst FAS participants 
with a PlexiQOL total score at baseline and at least one post-baseline total score.
Intercurrent events are addressed as follows:

Post randomised study intervention discontinuation PlexiQOL scores will not be 
collected and will be modelled through direct likelihood techniques assuming a 
hypothetical strategy to the intercurrent event of randomised study intervention 
discontinuation prior to end of cycle 12 due to any reason. 

PlexiQOL scores after early crossover from placebo to selumetinib in participants 
with documented progression on imaging (as determined by ICR per REiNS criteria) 
will be set to missing assuming a while-on-treatment strategy to the intercurrent event 
of early crossover from placebo to selumetinib. 

PlexiQOL scores after the first 28 days of a prolonged study intervention interruption 
until day prior to study intervention recommencement will be set to missing assuming 
a while-on-treatment strategy to the intercurrent event of prolonged study intervention 
interruption.

PlexiQOL scores after a target PN resection will be included in the analysis assuming 
a treatment policy approach to the intercurrent event of target PN resection. 
The response variable for a specific cycle will be the PlexiQOL change from baseline, defined 
as the PlexiQOL total score at that cycle minus the baseline PlexiQOL total score.   

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The difference in the mean change from baseline at Cycle 12 will be analysed for PlexiQOL 
using a MMRM analysis. The MMRM model will include treatment, cycle number and 
geographical region as categorical fixed effects, the baseline PlexiQOL total score as a 
continuous covariate and treatment-by-cycle number and baseline PlexiQOL total score-by-
cycle number interactions. Parameters will be estimated with the restricted maximum 
likelihood (REML) approach and the Kenward-Roger approximation is used to estimate the 
degrees of freedom.  An unstructured covariance matrix will be used to allow for unequal 
treatment variance and to model the correlation between different treatment measurements 
within the same subject. If the fit of the unstructured covariance structure fails to converge, 
the following covariance structures will be used in order until convergence is reached: toeplitz 
with heterogeneity, autoregressive with heterogeneity, toeplitz, autoregressive and compound 
symmetry. 
Missingness will be examined, and sensitivity analyses will be performed as appropriate. In 
addition, supplementary analyses for alternative estimands will be explored. 
Sample Size
With regard to the primary endpoint, a sample size of 73 participants per arm will have >99% 
power to detect the difference between selumetinib ORR of 20% and placebo ORR of 0%, 
considering a two-sided alpha of 5%.
Forty-two participants per arm are required for the study to have 90% power to detect a 
treatment difference of ≥ -2 in the 1st key secondary endpoint of the mean change from 
baseline of PAINS-pNF chronic target PN pain intensity score at Cycle 12 (assuming an SD of 
2.8) in favour of selumetinib compared with placebo at a two-sided alpha level of 5%. To 
allow for approximately 20% drop out (ie, participants without at least one postbaseline 
average cycle PAINS-pNF chronic target PN pain score), 106 participants with baseline 
PAINS-pNF chronic target PN pain score ≥ 3 will be randomised in a 1:1 selumetinib:placebo 
allocation, ie, 53 participants per arm. In addition, approximately 40 participants with NF1 
and a PAINS-pNF chronic target PN pain score of < 3 at baseline (including those with no PN 
pain) will be randomised 1:1 to receive selumetinib or placebo, ie, 20 participants per arm. 
There is no formal sample size calculation regarding randomising 40 participants with 
baseline PAINS-pNF chronic target PN pain score of < 3; however, this is deemed sufficient to 
ensure the target population of adults with NF1 and symptomatic, inoperable PN (including 
those with little or no baseline PN pain) are represented.
Multiplicity Testing Procedure
To preserve the overall type 1 error (familywise error rate) at 5% (two-sided) in the strong 
sense, the MTP (described in Figure 1) including the primary endpoint (ORR by end of Cycle 

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16) and the key secondary endpoints (change from baseline in PAINS-pNF chronic target PN 
pain intensity at Cycle 12 and change from baseline in PlexiQOL total score at Cycle 12) will 
be implemented at the interim analysis (DCO1) and primary analysis (DCO2).
Figure 1
Multiple Testing Procedure
DCO, data cut off; FAS, Full analysis set; H0, null hypothesis; ORR, Objective response rate, PAINS-pNF, PAin 
INtensity Scale for plexiform neurofibromas; PlexiQOL, Plexiform Neurofibromas Quality of Life; PN, 
plexiform neurofibromas.
Safety data will be summarised descriptively and will not be formally analysed unless 
otherwise specified.

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1.2
Schema
Figure 2
Study Design
a
Symptoms may include (but not limited to) pain, motor morbidity, disfigurement.
bid, twice daily; DCO, data cut-off; IA, interim analysis; LPD, last participant dosed; NF1, Neurofibromatosis 
type 1; PA, primary analysis; PN, Plexiform Neurofibroma; R Randomisation. From the end of Cycle 24 (Cycle 
25 Day 1) participants will not be required to continue to observe the fasting restriction.
1.3
Schedule of Activities
The procedures for this study are presented in the SoA (Table 1 and Table 2).

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Table 1
Schedule of Activities
Intervention Period
Procedure
Screeninga
Baseline
pre-dose 
C1D1
C1
D8
C1
D28
C2 
D28
C4 
D28
C6
D28
C8 
D28
C10 
D28
C12 
D28
C16 
D28
C20 
D28
C24 
D28W
C30 b
D28
onwards
EoT c
Safety 
Follow-up 
(30 days 
after last 
dose) 
Ref in 
CSP
Study Day 
Day – 28 to 
Day – 1
Day
1
Day 
8
Day
28
Day
56
Day
112
Day
168
Day
224
Day
280
Day
336
Day
448
Day
560
Day
672
Window (days)
Day 
4-14
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
+ 7
+ 7
Informed 
consent: main 
study d
X
A 3
Informed 
consent genetic 
sample and 
analysis 
(optional)
X
8.7
Inclusion and 
exclusion 
criteria
X
X
5.1
5.2
Randomisation e
X
6.3
Demography
X
5.1
Disease 
characteristics f
X
5.1
Full physical 
examination g
X
X h
8.2.1
Targeted 
physical 
examination g
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.1
Height i
X
8.2.2

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Table 1
Schedule of Activities
Intervention Period
Procedure
Screeninga
Baseline
pre-dose 
C1D1
C1
D8
C1
D28
C2 
D28
C4 
D28
C6
D28
C8 
D28
C10 
D28
C12 
D28
C16 
D28
C20 
D28
C24 
D28W
C30 b
D28
onwards
EoT c
Safety 
Follow-up 
(30 days 
after last 
dose) 
Ref in 
CSP
Study Day 
Day – 28 to 
Day – 1
Day
1
Day 
8
Day
28
Day
56
Day
112
Day
168
Day
224
Day
280
Day
336
Day
448
Day
560
Day
672
Window (days)
Day 
4-14
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
+ 7
+ 7
Weight and 
BSA i
X
X h
X
X
X
X
X
X
X
X l
8.2.2
Medical history 
(past and 
current medical 
conditions)
X
X h
5.1
5.2
Clinical safety 
laboratory 
assessments 
(clinical 
chemistry, 
haematology, 
urinalysis)
X
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.6
Genomics 
initiative 
optional, 
exploratory 
genetic blood 
sample j
X
8.7
12-lead ECG k
X
X h
X l
8.2.4
ECHO/cardiac 
MRI l
X
X
X
X
X
X
X
X
X l
X l
8.2.5

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Table 1
Schedule of Activities
Intervention Period
Procedure
Screeninga
Baseline
pre-dose 
C1D1
C1
D8
C1
D28
C2 
D28
C4 
D28
C6
D28
C8 
D28
C10 
D28
C12 
D28
C16 
D28
C20 
D28
C24 
D28W
C30 b
D28
onwards
EoT c
Safety 
Follow-up 
(30 days 
after last 
dose) 
Ref in 
CSP
Study Day 
Day – 28 to 
Day – 1
Day
1
Day 
8
Day
28
Day
56
Day
112
Day
168
Day
224
Day
280
Day
336
Day
448
Day
560
Day
672
Window (days)
Day 
4-14
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
+ 7
+ 7
Ophthalmology 
examination m
X
X
X
X
X m
X
X m
8.2.7
Performance
status (ECOG)
X
X h
X
X
X
X
X
X
X
X
8.2.8
Pregnancy test n
X
X
Every cycle
X
X
8.2.6
Vital signs o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.3
PN assessments 
using 
volumetric 
MRI p
X
X
X
X
X
X
X
X
X
8.1.1
8.1.2
PAINS-pNF q
Daily e-Diary
8.1.8
PN pain 
medication 
diary q
Daily e-Diary
8.1.8
Drug Diary r
Daily e-Diary
6.4
Investigator 
assessment of 
changes in pain 
medication s
X
X
X
X
X
X
X
8.1.8.
3

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Table 1
Schedule of Activities
Intervention Period
Procedure
Screeninga
Baseline
pre-dose 
C1D1
C1
D8
C1
D28
C2 
D28
C4 
D28
C6
D28
C8 
D28
C10 
D28
C12 
D28
C16 
D28
C20 
D28
C24 
D28W
C30 b
D28
onwards
EoT c
Safety 
Follow-up 
(30 days 
after last 
dose) 
Ref in 
CSP
Study Day 
Day – 28 to 
Day – 1
Day
1
Day 
8
Day
28
Day
56
Day
112
Day
168
Day
224
Day
280
Day
336
Day
448
Day
560
Day
672
Window (days)
Day 
4-14
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
+ 7
+ 7
PII-pNF
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.8
PGIS
X
X
X
X
X
X
X
X
8.1.8
PGIC t
X
X
X
X
X
X
X
X
8.1.8
PROMIS 
physical 
function items
X
X
X
X
X
X
X
X
X
X
8.1.8
PedsQL (NF1 
module acute 
Version 3.0 –
adult report) 
Skin Sensations 
domain
X
X
X
X
X
X
X
X
X
X
8.1.8
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
8.1.8
PlexiQoL
X
X
X
X
X
X
X
X
X
X
8.1.8
Dispense study 
intervention
X
X
X
X
X
X
X
X
X
X
X
X
6.1
Return study 
intervention and 
compliance 
check
X
X
X
X
X
X
X
X
X
X
X
X
6.4

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Table 1
Schedule of Activities
Intervention Period
Procedure
Screeninga
Baseline
pre-dose 
C1D1
C1
D8
C1
D28
C2 
D28
C4 
D28
C6
D28
C8 
D28
C10 
D28
C12 
D28
C16 
D28
C20 
D28
C24 
D28W
C30 b
D28
onwards
EoT c
Safety 
Follow-up 
(30 days 
after last 
dose) 
Ref in 
CSP
Study Day 
Day – 28 to 
Day – 1
Day
1
Day 
8
Day
28
Day
56
Day
112
Day
168
Day
224
Day
280
Day
336
Day
448
Day
560
Day
672
Window (days)
Day 
4-14
± 3
± 3
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
+ 7
+ 7
PK blood 
samples u
X
8.5.1
AEs v
X
X
=================================================================================
8.3
Concomitant 
medication/ 
procedures
X
X
=================================================================================
6.5
a
The 28-day screening period will commence on the date the ‘Screening Visit’ transaction is registered in IRT system. Visit schedule should always be 
calculated in relation to C1D1. Visits should not be skipped or overwritten in IRT. If a visit (+ visit window) is missed, the visit should be completed as the 
earliest opportunity. If there is a long gap between the scheduled and actual visit, please check with global study team how visits are to be recorded.
b
From Cycle 30 onwards, for all participants remaining on study intervention, assessments will be performed every 6 cycles with the exception of 
ophthalmic assessments (see footnote l) and pregnancy assessments (see footnote m).
c
The 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 decision to discontinue treatment permanently has been made. If 
EoT is >30 days after last treatment dose, then the EoT assessments can also function as the 30-Day Safety follow-up visit.
d
Screening tests should be performed within 28 days before the first administration of study intervention, unless otherwise indicated. Written informed 
consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. 
e
Every effort should be made to minimise the time between randomisation and starting treatment (maximum interval of 3 business days of randomisation).
f
Assessment of baseline disease characteristics includes documenting location of the target and non-target PN (if applicable) and any PN-related symptoms 
and results of any previous genetic testing for NF1.

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g
The full physical examination includes an assessment of the following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities), urogenital, dermatological, gastrointestinal, 
endocrine, haematologic/lymphatic and neurological systems. Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology. The targeted physical exam will include, at a minimum, assessments of the general appearance, respiratory and 
cardiovascular systems, skin and abdomen (liver and spleen). 
h
If screening assessments have been performed within 14 days prior to starting study intervention, they do not have to be repeated at Cycle 1 Day 1 if the 
participant’s condition has not changed. A stable participant's condition since previous assessment should be documented in medical records.
i
Height and weight measurements will be performed in light clothing and with shoes off. Body surface area should be calculated. Height, weight and BSA 
may be measured more frequently, if indicated. BSA should be calculated using Mosteller formula, see Section 8.2.2.
j
The sample for genetic research will be obtained at Day 1 pre-dose. If, for any reason, the sample is not drawn at Day 1, it may be taken at any visit until the 
last study visit. Only one sample should be collected per participant for genetics during the study.
k
Performed at screening and baseline and then as clinically indicated. Participants should be semi-supine and at rest for at least 5 minutes prior to recording 
the ECG. 
l
The modality of the cardiac function assessments must be consistent for a given participant. The participant should be examined using the same machine 
and operator throughout the study wherever possible. Echocardiogram/cardiac MRI is not required at EoT visit if the participant has had an echo/cardiac 
MRI within 4 weeks prior to study intervention discontinuation, unless clinically indicated. Echocardiogram/cardiac MRI is only required at 30 day safety 
follow-up in participants who have abnormal findings at the time of selumetinib discontinuation/ EoT visit. 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 or cardiac MRI, 
ECG, vital signs, and weight performed at the 30 day safety follow-up.
m
Ophthalmologic assessments may be performed more often, if clinically indicated. After 12 cycles, ophthalmological assessment will be performed every 
12 cycles. Only required at the Safety Follow-up visit if abnormal findings at EoT assessment.
n
Pregnancy testing will be performed at screening, Cycle 1 Day 1, and every cycle throughout the entire exposure period, in women of childbearing potential 
only. A serum pregnancy test is required at screening, following that a urine or serum pregnancy test is acceptable. Where a pregnancy test is the only 
assessment for a cycle, a clinic visit is not required as the test may be performed offsite. The site should obtain the test result from the participant prior to 
the next onsite visit.
o
Temperature (same method to be used throughout the study), pulse rate, oxygen saturation by pulse oximetry, respiratory rate, and BP will be assessed. 
Assessments of BP and pulse rate should be assessed in a sitting position and preceded by at least 5 minutes of rest in a quiet setting without distractions 
(eg, television, cell phones). Manual techniques will be used only if automated devices are not available. The average of 3 BP readings, taken consecutively 
at intervals of at least one minute apart will be recorded on the eCRF.
p
The PN assessments will be performed at screening and every 4 cycles (16 ± 1 weeks) up to Cycle 24 (ie, at Cycle 4, 8, 12, 16, 20, and 24). After 24 cycles, 
PN assessments will be performed every 6 cycles (24 ± 1 weeks) as long as the participant remains on study intervention. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has not progressed, the subsequent assessments at the next 
scheduled visit must be performed. All volumetric MRI scans should be performed relative to Cycle 1 Day 1, ie the time course should not change if the 
participant experiences a dose interruption or there are delays in previous scan visits.
q
PAINS-pNF scores and PN pain medication should be collected on the daily e-Diary during screening, the intervention period and up to EoT. Chronic target 
PN pain intensity PAINS-pNF scores must be recorded for at least 4 days out of 7 days for at least 2 weeks during the screening period for a participant to 
be considered eligible for study. 
r
Participants will complete a daily drug diary during the interventional period to record whether study intervention was taken as instructed.

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s
The investigator will record in the eCRF if the participant’s analgesic requirement has changed compared to baseline since it was last assessed. Assessments 
will be performed at site visits with additional telephone assessments at Cycle 3, Day 28; Cycle 5, Day 28; Cycle 7, Day 28; Cycle 9 Day 28 and Cycle 11 
Day 28 (see Table 2).
t
PGIC 1 ‘since your last visit to the study site’ should be assessed at site visits Cycle 1, Day 28; Cycles 2, 4, 6, 8, 10, 12; PGIC 2 ‘since starting the study 
medication’ should be assessed at Cycle 12 or EoT if the participant discontinues pre-Cycle 12. 
u
Blood samples to measure selumetinib and N-desmethyl selumetinib metabolite will be collected on Cycle 1 Day 8: Pre-Dose, 0.5 h, 1.5 h, 3 h, 6 h and 8 h 
post-dose. For operational reasons the PK sampling can take place on any day between Day 4 and Day 14 as long as the participant has received 
3 consecutive days of dosing immediately prior to the PK day. Every effort should be made to conduct PK sampling within the Day 4 to Day 14 window.
However, if for unforeseen reasons this is not possible, PK sampling can be performed ideally within the first cycle but no later than Cycle 12, provided the 
participant has received 3 consecutive days of dosing immediately prior to the PK day. The selumetinib dose dates and times must be recorded accurately 
on the day preceding the PK sample day and on the PK sample day.
v
Adverse events will be collected from the time of signing the ICF, throughout the treatment period, and including the follow-up period. Adverse events will 
also be collected at additional telephone assessments on Cycle 3, Day 28; Cycle 5, Day 28; and Cycle 7, Day 28; Cycle 9 Day 28 and Cycle 11 Day 28, as 
per Table 2.
w
From the end of Cycle 24 (Cycle 25 Day 1) participants will not be required to continue to observe the fasting restriction, i.e participant can eat at any time 
point in relation to each selumetinib intake.
Each treatment cycle is 28 days. Assessments will be performed at the end of each cycle. Study intervention will be dispensed after all assessments have been 
performed and evaluated by the investigator. Participant’s second dose on the day of their on-site visit can be taken from newly dispensed study intervention. 
Treatment will not be held while end of cycle evaluations are ongoing. Note: Data collection following study analysis until the end of the study is described in 
Section 8.
AE, adverse event; BSA, body surface area; BP, blood pressure; CSP, clinical study protocol; C, cycle; D, day; ECG, electrocardiogram; 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; EoT, end of treatment; EQ 5D 5L, EuroQol 5-Dimension 5-level; ICF, informed consent 
form; IRT, Interactive Response Technology; MRI, magnetic resonance imaging; NF1, neurofibromatosis type 1; PAINS-pNF, PAin INtensity Scale for 
Plexiform Neurofibromas; PedsQL, Paediatric Quality of Life Inventory; PGIC, Patient Global Impression of Change; PGIS, Patient Global Impression of 
Severity; PII-pNF, Pain Interference Index- Plexiform Neurofibroma; PK, pharmacokinetic(s); PlexiQoL, Plexiform Neurofibromas Quality of Life; PN, 
plexiform neurofibroma; PROMIS, Patient-Reported Outcomes Measurement Information System.

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Table 2
Schedule of Telephone Assessments
Intervention period
Cycle 3
Day 28
Cycle 5
Day 28
Cycle 7 
Day 28
Cycle 9
Day 28
Cycle 11 
Day 28
Window (days)
± 7
± 7
± 7
± 7
± 7
Investigator assessment of 
changes in pain medication
X
X
X
X
X
Adverse events 
X
X
X
X
X
Concomitant medication/ 
procedures
X
X
X
X
X

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2
INTRODUCTION
Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor with a short 
half-life that is being developed for the treatment of NF1-PN.
2.1
Study Rationale
Selumetinib has been shown to be effective in the treatment of paediatric patients with NF1 
who have symptomatic, inoperable PN and is approved in the US for the treatment of 
paediatric patients aged ≥ 2 years of age. Plexiform neurofibromas, whilst typically present at 
birth, can continue to manifest through late adolescence and early adulthood 
(Williams et al 2009) and are often associated with significant clinical symptoms including 
pain and motor dysfunction (Gross et al 2018). As spontaneous PN shrinkage and spontaneous 
resolution of symptoms associated with PN has been shown to be extremely unlikely 
(Akshintala et al 2020, Gross et al 2018), adults with NF1-PN continue to have a significant 
unmet need. This study will aim to inform the benefit risk profile of selumetinib in adults with 
NF1 who have symptomatic, inoperable PN.
2.2
Background
Neurofibromatosis Type 1 is a rare, autosomal dominant genetic disorder that is caused by 
germline mutations in the NF1 tumour suppressor gene (17q11.2), which encodes the tumour 
suppressor protein neurofibromin 1. Neurofibromin 1 is a GTPase-activating protein that 
promotes the conversion of active RAS GTP to inactive RAS guanosine 5’-diphosphate, 
thereby functioning as a negative regulator of the RAS proto-oncogene, which is a key 
signalling molecule in the control of cell growth (Gutmann et al 2012). Neurofibromin 1 
mutation that leads to loss of function results in a failure to inactivate RAS. 
Approximately half of NF1 cases are familial, with penetrance being 100%, and the remainder 
are the result of de novo (spontaneous) mutations (Evans et al 2010). Features of the disorder 
typically appear in early childhood and are fully penetrant by adulthood (Stewart et al 2018).
Neurofibromatosis Type 1 is characterised by progressive cutaneous, neurological, skeletal, 
and neoplastic manifestations early in life and the associated clinical signs and symptoms can 
be severe. Affected individuals start life with one mutated (non-functional) 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 formation 
of tumours (including PN), by acquisition of a somatic NF1 mutation in selected cells 
(Gutmann et al 2013; Ruggieri and Packer 2001). Patients with NF1 have an increased risk of 
developing tumours of the central and peripheral nervous system. 

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Neurofibromas are benign Schwann cell tumours composed not only of neoplastic Schwann 
cells but also of non-neoplastic fibroblasts, mast cells, macrophages, endothelial cells, 
pericytes, and perineural cells. Plexiform neurofibromas are one of the most common benign 
tumours, occurring in approximately 20% to 50% of patients (Korf 1999; Mautner et al 2008).
Plexiform neurofibromas can have complex shapes and sometimes reach very large size with 
some documented as being 20% of body weight (Korf 1999; Mautner et al 2008). Plexiform 
neurofibromas may develop along nerves anywhere in the body.
Patients may have one or multiple PNs that result in clinical impact such as pain, neurological 
and motor dysfunction, airway compromise, visual impairment, or disfigurement. The severity 
may range from mild, with modest impact on daily activities, to severe. The symptoms or 
impact from the presence and growth of PNs are collectively termed PN associated symptoms 
(also referred to as morbidities in the literature and clinical community) and spontaneous 
resolution of these symptoms once developed has been shown to be extremely unlikely 
(Gross et al 2018).
Pain associated with PNs can interfere with daily activities despite analgesia 
(Wolters et al 2015). Heaney et al 2019 reported the impact of PNs on need fulfilment in 
adults. Patients reported restrictions on their independence due to the unpredictable nature of 
their PN symptoms. This results in greater dependence on family and friends, particularly as 
those with PN-related pain and discomfort found it difficult to devote attention to other issues. 
This also impacts on their need for role fulfilment as it leads to inability to work or take part in 
sports or hobbies. The NCI has conducted extensive qualitative research in order to 
understand the pain experience of adult patients with NF1 and PNs and to modify the standard 
NRS-11 to be more appropriate for this population. They found that patients with NF1-PN 
experience two types of PN-related tumour pain- chronic pain and spike pain: 

Chronic tumour pain (also known as usual tumour pain) is tumour pain that is present 
most of the time (described as “constantly there”, “it’s going to always hurt”, “pain is 
every single day”).

Spikes of tumour pain (also known as episodic tumour pain) are sudden bursts of tumour 
pain that may occur spontaneously or in response to a stimulus (described as “a shock 
pain”, “like an electricity pain, it will come really fast, and then it leaves”, “if I hit against 
something”).
The tool developed by the NCI is known as PAINS-pNF and based on the above research has 
2 items, one assessing participants’ experience of chronic PN-related pain intensity, and the 
other their experience of spikes of PN-related pain intensity, both for a target PN-location.

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Selumetinib is a potent, selective, allosteric inhibitor of MEK that is non-competitive with 
respect to ATP, licensed for development by AstraZeneca Pharmaceuticals from Array 
BioPharma. Selumetinib is being co-developed by AstraZeneca and Merck & Co. 
Selumetinib blocks MEK activity and inhibits growth of RAF-MEK-ERK pathway activated 
cell lines. Therefore, MEK inhibition can block the proliferation and survival of tumour cells 
in which the RAF-MEK-ERK pathway is activated. Neurofibromin-1 (encoded by the NF1 
gene) is a negative regulator of RAS and therefore loss of function mutations in NF1 result in 
activation of the RAF-MEK-ERK pathway. In genetically modified mouse models of NF1 that 
generate neurofibromas that recapitulate the genotype and phenotype of human type 1 
neurofibromas, oral dosing of selumetinib inhibits ERK phosphorylation, reduces 
neurofibroma volume, proliferation, number and growth. Selumetinib is being developed as a 
treatment for paediatric and adult patients with NF1 who have symptomatic PNs.
Selumetinib received approval in the US in April 2020 for the treatment of paediatric patients 
2 years of age and older with NF1 who have symptomatic, inoperable PN based on the 
Phase II Stratum 1 data of the SPRINT study (D1532C00057), coordinated by NCI POB 
under CTEP sponsorship and conducted in the US. Supportive efficacy data were provided by 
the Phase I data of the SPRINT study (Study 8799; NCI 11 C 0161, D1532C00057).
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of selumetinib is provided in the Investigator’s Brochure.
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 3. Guidance and algorithms for the management of these risks are described in 
Appendix H.

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Table 3
Risk Assessment
Potential risk of clinical 
significance
Rationale for risk
Mitigation strategy
Transaminase increases
Increases in serum ALT and AST levels have been observed 
in clinical studies with selumetinib. While the reported 
events have been typically low grade and no cases of Hy’s 
law have been seen, elevated transaminase is a class effect 
and should be closely monitored to detect early liver 
toxicity.
Exclusion of participants with known moderate or severe 
hepatic impairment. Exclusion of participants with any 
evidence of severe uncontrolled systemic liver disease, 
including those with known hepatitis B, hepatitis C, or 
abnormal liver function test as transaminases 
> 2.5 × ULN and total bilirubin > 1.5 × ULN or 
> 3 × ULN in the presence of documented Gilbert’s 
syndrome (unconjugated hyperbilirubinemia). Liver 
function test monitoring will take place according to the 
SoA.
Increased BP
Increases in systolic BP and diastolic BP have been 
observed in clinical studies with selumetinib. Adverse 
events were generally CTCAE Grade 1 or 2 and 
asymptomatic, but some patients required amendment or 
initiation of antihypertensive medication. Study population 
has increased risk of NF1 vasculopathy, therefore these 
events should be closely monitored.
Patients with uncontrolled hypertension (at screening: BP 
≥ 140/90 mmHg despite optimal therapy) would be 
excluded from the trial. Regular monitoring of vital signs 
is included in the SoA.
Increased exposure in Asian 
participants
Increased systemic exposure has been seen in adult Asian 
subjects, although there is considerable overlap with 
Western subjects when corrected for body weight.
No specific adjustment to the starting dose is 
recommended for Asian patients, however, these patients 
should be closely monitored for AEs.
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CK, creatine kinase; CSR, central serous retinopathy; 
CTCAE, Common Terminology Criteria for Adverse Events; IOP, intraocular pressure; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; 
MRI, magnetic resonance imaging; NF1, neurofibromatosis type 1; RPED, retinal pigment endothelial detachment; PN, plexiform neurofibroma; RVO, retinal 
vein occlusion; SoA, schedule of activities; ULN, upper limit of normal.

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Table 4
Objectives and Endpoints
Objectives
Estimands descriptions/Endpoints
To demonstrate the effectiveness of selumetinib by 
assessment of DoR in participants with NF1 who 
have symptomatic, inoperable PN.
The duration of response will be defined as the 
time from the date of first documented response 
(which is subsequently confirmed) until date of 
documented progression by ICR per REiNS 
criteria or death due to any cause. The analysis 
will include all participants randomised to 
selumetinib with measurable target PN at 
baseline per ICR who received at least one dose 
of selumetinib and with a confirmed CR or 
confirmed PR prior to study intervention 
discontinuation. Duration of response will be 
derived using while on-treatment MRI 
volumetric assessments.
To demonstrate the effectiveness of selumetinib by 
assessment of PFS in participants with NF1 who 
have symptomatic, inoperable PN.
Progression free survival is defined as the time 
from the date of first selumetinib dose until date 
of progression by ICR per REiNS criteria or 
death (due to any cause). The analysis 
will include all participants randomised to 
selumetinib with measurable target PN at 
baseline per ICR who received at least one dose 
of selumetinib. Progression free survival will be 
derived using while on-treatment MRI 
volumetric assessments.
To demonstrate the effectiveness of selumetinib by 
assessment of TTP in participants with NF1 who 
have symptomatic, inoperable PN.
Time to progression is defined as the time from 
the date of first selumetinib dose until date of 
documented objective disease progression by 
ICR per REiNS criteria. The analysis will include 
all participants randomised to selumetinib with 
measurable target PN at baseline per ICR who 
received at least one dose of selumetinib. Time 
to progression will be derived using while 
on-treatment MRI volumetric assessments.

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Table 4
Objectives and Endpoints
Objectives
Estimands descriptions/Endpoints
To demonstrate the effectiveness of selumetinib by 
assessment of TTR in participants with NF1 who 
have symptomatic, inoperable PN.
Time to response is defined as the time from date 
of first selumetinib dose until the date of first 
documented objective response (which is 
subsequently confirmed), by ICR per REiNS 
criteria. The analysis will include all participants 
randomised to selumetinib with measurable 
target PN at baseline per ICR and who received 
at least one dose of selumetinib and with a 
confirmed CR or confirmed PR prior to 
selumetinib discontinuation. Data obtained from 
first dose up until progression, or the last 
evaluable assessment in the absence of 
progression, will be included in the assessment 
of TTR. Time to response will be derived using 
while on-treatment MRI volumetric assessments.
To demonstrate the effect of selumetinib relative to 
placebo by assessment of percentage change from 
baseline in target PN volume in participants with 
NF1 who have symptomatic, inoperable PN.
Difference in best percentage change from 
baseline in target PN volume by ICR per REiNS 
criteria between selumetinib and placebo during 
the randomised period. The analysis will include 
all participants randomised to study intervention 
with measurable target PN at baseline per ICR. 
The best percentage change from baseline in 
target PN volume will be derived using while 
on-treatment MRI volumetric assessments during 
the randomised period.

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Table 4
Objectives and Endpoints
Objectives
Estimands descriptions/Endpoints
To compare the effect of selumetinib relative to 
placebo by assessment of chronic target PN pain 
palliation and time to chronic target PN pain 
palliation in participants with a PAINS-pNF chronic 
target PN pain score of ≥ 3 at baseline.
Chronic target PN pain palliation is defined as 
improvement of ≥ 2 in average cycle PAINS-
pNF chronic target PN pain intensity score and 
no increase in chronic PN pain medication 
compared to baseline for that cycle. Pain 
palliation will be assessed in participants with a 
PAINS-pNF chronic target PN pain score of ≥3 
at baseline.

Difference in proportion of participants with 
chronic target PN pain palliation between 
selumetinib and placebo at post-baseline 
cycles and overall over the randomised 
treatment period.

Time to chronic target PN pain palliation is 
defined as the time from the first dose of 
study drug until the cycle of chronic target 
PN pain palliation.
To compare the effect of selumetinib relative to 
placebo by assessment of pain medication compared 
with baseline.
Difference in change from baseline in pain 
medication use (as reported using the eDiary and 
as assessed by the investigator) between 
selumetinib and placebo at post-baseline cycles 
and overall over the randomised treatment 
period.
To compare the effect of selumetinib relative to 
placebo by assessment of pain interference compared 
with baseline.
Difference in change from baseline in PII-pNF 
pain interference total score between selumetinib 
and placebo at post-baseline cycles and overall 
over the randomised treatment period.
To compare the effect of selumetinib relative to 
placebo by assessment of physical functioning 
compared with baseline.
Difference in change from baseline in PROMIS 
Physical Function scores between selumetinib 
and placebo at post-baseline cycles and overall 
over the randomised treatment period.
To compare the effect of selumetinib relative to 
placebo by further assessment of HRQoL compared 
with baseline.
Difference in change from baseline in the Skin 
Sensations domain from the PedsQL (NF1 
module acute Version 3.0 – adult report) 
between selumetinib and placebo at post-baseline 
cycles and overall over the randomised treatment 
period.

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Table 4
Objectives and Endpoints
Objectives
Estimands descriptions/Endpoints
To compare the effect of selumetinib relative to 
placebo by assessment of health status compared 
with baseline.
Difference in change from baseline in EQ-5D-5L 
between selumetinib and placebo at post-baseline 
cycles and overall over the randomised treatment 
period.
Difference in change from baseline in EQ-VAS 
between selumetinib and placebo at post-baseline 
cycles and overall over the randomised treatment 
period.
To evaluate the effect of selumetinib by assessment 
of physical functioning compared with baseline.
Change from baseline in PROMIS Physical 
Function items.
To evaluate the effect of selumetinib by assessment 
of HRQoL compared with baseline.
Change from baseline in PlexiQoL.
Change from baseline in the Skin Sensations 
domain from the PedsQL (NF1 module acute 
Version 3.0 – adult report).
To evaluate the effect of selumetinib by assessment 
of health status compared with baseline.
Change from baseline in EQ-5D-5L 
(standardised measure of health status). Five 
dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). 
Change from baseline in EQ-VAS.
To assess the PK of selumetinib.
•
Plasma concentrations and PK parameters of 
selumetinib including, but not limited to: 

Cmax, AUC(0-6), AUC(0-8), AUClast, 
CL/F, Vss/F, tmax, tlast derived after 
multiple dose administration.
•
Plasma concentrations and PK parameters of 
N desmethyl selumetinib including, but not 
limited to:

Cmax, AUC(0-6), AUC(0-8), AUClast, 
tmax , tlast derived after multiple dose 
administration.

MPAUC and MPCmax after multiple dose 
administration.
•
Population PK-pharmacodynamic analyses will 
be completed to investigate the selumetinib 
exposure-response relationship for safety and 
efficacy. The analyses will be reported 
separately from the Clinical Study Report.

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4
STUDY DESIGN
4.1
Overall Design
This is a Phase III, multicentre, international study with a parallel, randomised, double-blind, 
placebo-controlled, 2 arm design to assess the efficacy and safety of selumetinib in adult 
participants with NF1 who have symptomatic, inoperable PN.
The study is intended to represent the population of adult patients with NF1 who have 
symptomatic, inoperable PN. Approximately 146 adult participants will be randomised who 
have NF1 and inoperable PN that cause symptoms including, but not exclusively, pain, 
disfigurement, airway impairment, and motor or bowel and/or bladder dysfunction. In order to 
achieve the global target of randomising 146 participants, this study will enrol approximately 
212 participants at approximately 46 sites across 13 countries.
During screening, a single target PN will be selected by the Investigator and is defined as the 
clinically most relevant PN, which has to be measurable by volumetric MRI analysis (ie, a PN 
of at least 3 cm measured in one dimension, which can be seen on at least 3 imaging slices, 
and has a reasonably well-defined contour). If there is a second PN that is also considered 
clinically relevant and is measurable, the investigator may select this as a non-target PN; only 
one non-target PN can be selected. 
As PNs are often associated with multiple co-morbidities such as pain and motor dysfunction, 
these elements will be assessed using various patient-reported outcome tools.
Pain, associated with the target PN, will be assessed using the PAINS-pNF, a modified 
NRS-11 pain scale for use in NF1-PN that measures the participant’s usual chronic tumour 
pain as well as sudden bursts of tumour pain that may occur, known as spikes of tumour pain.
Chronic PN pain and spike pain medication use will be assessed during the study and all 
participants should have stable chronic PN pain medication use at baseline, as assessed by the 
investigator. Stable chronic PN pain medication is defined as no clinically significant changes 
to prescribed chronic PN pain medication within 28 days prior to study enrolment or planned 
at the time of study enrolment. All participants will be expected to complete PN pain intensity 
assessments using the eDiary in the screening period. During this time, participants must 
complete their pain diary for at least 4 days out of 7 days for at least 2 weeks in order to 
determine the participant’s average baseline chronic target PN pain intensity score which is 
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Following a screening period lasting up to 28 days, approximately 146 eligible adult 
participants will be randomised in a 1:1 ratio to one of the following intervention groups:

Arm A: selumetinib 25 mg/m2 orally bid

Arm B: placebo orally bid
Randomisation will be stratified by average baseline PAINS-pNF chronic target PN pain score
and geographical region. The number of participants randomised will be capped at 
approximately 106 participants with an average baseline PAINS-pNF chronic target PN pain 
score ≥3 and approximately 40 participants with an average baseline PAINS-pNF chronic 
target PN pain score < 3.
Participants randomised to selumetinib will receive selumetinib 25 mg/m2 orally bid (based on 
BSA, capped at 50 mg bid when BSA is ≥ 1.9 m2) in 28-day cycles until a selumetinib 
discontinuation criterion is met. Participants randomised to placebo will receive placebo orally 
bid and will be crossed over to selumetinib treatment after the end of Cycle 12. Selumetinib 
capsules will be administered using BSA-based dosing. If it is anticipated that 20% or more of 
participants (across blinded study intervention groups) withdraw prior to the end of Cycle 16, 
for reasons other than progression, then recruitment rates withstanding, enrolment will 
continue to randomise at least 50% of the total number of drop-out participants to ensure the 
primary endpoint is adequately powered.
The interim analysis (DCO1) will occur after the 100th randomised participant has had the 
opportunity to complete their end of Cycle 16 assessment and the primary analysis (DCO2) 
will occur after the last participant dosed (the last participant receiving first dose) has had the 
opportunity to complete their end of Cycle 16 assessment. If the interim analysis DCO 
(DCO1) is due to take place within approximately 4 months of the primary analysis DCO 
(DCO2), then the interim analysis may not be performed and only the primary analysis will be 
performed. The primary analysis of ORR will take place at the end of Cycle 16 landmark and 
will be assessed in all randomised participants with measurable target PN at baseline per ICR. 
The summary measure of the 1st key secondary endpoint is the difference in the mean change 
from baseline in PAINS-pNF chronic target PN pain intensity score at Cycle 12 between 
selumetinib compared to placebo. This will be assessed in participants with a PAINS-pNF 
chronic target PN pain intensity score of ≥ 3 at baseline and at least one postbaseline average 
cycle PAINS-pNF chronic target PN pain intensity score. The summary measure of the 2nd key 
secondary endpoint is the difference in the mean change from baseline in PlexiQOL total 
score at Cycle 12 between selumetinib compared to placebo. This will be assessed in 
participants with a baseline PlexiQOL total score and at least one post-baseline PlexiQOL 
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The final analysis (Final DCO) will occur approximately 24 cycles post last participant dosed. 
The proposed duration for the study is approximately 24 months from last participant dosed to 
provide mature efficacy data as well as further safety and tolerability data. 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 and in 
the absence of discontinuation criteria.
As each participant reaches the end of Cycle 24 (Cycle 25 Day 1), they will then be permitted 
to eat at any time point in relation to each selumetinib intake. Since participants will be not 
require continuing to observe the fasting restriction, they will be considered in fed state. The 
data obtained in the fed state will be analysed in line with the main study analysis. Refer to 
Section 5.2.1 for the definition of participant fed state.
If selumetinib is approved locally and reimbursed for use in adult patients with NF1 who have 
symptomatic, inoperable PN, participants should be switched to the commercial supply at the 
end of the study. However, if the participant is unable to access the commercial supply and 
they are still receiving clinical benefit, AstraZeneca and the Investigator will discuss how the 
participant could continue to receive selumetinib if he/she is benefiting from treatment.
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
and will be followed up for safety assessments 30 (+ 7) days after their last dose of study 
intervention (ie, the safety follow-up visit), unless EoT is performed more than 30 days after 
last treatment dose, then the EoT assessments can also function as the 30-Day Safety follow-
up visit.
4.2
Scientific Rationale for Study Design
Selumetinib has been shown to be effective in the treatment of paediatric patients with NF1 
who have symptomatic, inoperable PN and is approved in the US for the treatment of 
paediatric patients aged ≥ 2 years of age. Plexiform neurofibromas, whilst typically present at 
birth, can continue to manifest through late adolescence and early adulthood 
(Williams et al 2009) and are often associated with significant clinical symptoms including 
pain and motor dysfunction (Gross et al 2018). As spontaneous resolution of symptoms 
associated with PN has been shown to be extremely unlikely (Gross et al 2018), adults with 
NF1-PN continue to have a significant unmet need. This study will aim to inform the benefit 
risk profile of selumetinib in adults with NF1 who have symptomatic, inoperable PN. 
In the proposed study, the primary endpoint, ORR by end of Cycle 16, is assessed using 
volumetric MRI as determined by ICR per REiNS criteria. The REiNS expert group 
recommended volumetric MRI analysis as the most appropriate method to sensitively and 
reproducibly evaluate changes in PN size in clinical trials (Dombi et al 2013). It has been 
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NCI that whilst some gradual spontaneous PN shrinkage from maximal tumour volume 
occurred, this was only in a small number of PNs (8.8%) with no PN having ≥20% shrinkage 
per year (Akshintala et al 2020). Given that median TTR in adult patients is approximately 10 
months (O’Sullivan Coyne et al 2020), at least 16 cycles of follow-up is required to perform a 
meaningful comparison of ORR on selumetinib versus placebo. A limited placebo-controlled 
period (12 cycles) will be used in this study, which is considered an acceptable duration and 
still allows a robust comparison of ORR between treatment arms by end of Cycle 16 
landmark.
Based on feedback from patients and KOLs, symptom improvement as well as tumour 
shrinkage is of primary importance for adults with NF1-PN. Since PN-related pain is a 
frequently reported symptom (O’Sullivan Coyne et al 2020) it is considered that reduction in 
pain would be a key treatment benefit. In the SPRINT paediatric study PN pain improvement 
(mean reduction in NRS-11 PN pain score of ≥ 2 compared with baseline in those with an 
NRS-11 PN pain score of ≥ 3 at baseline) was observed after 2 cycles. Therefore, a 
randomised period until the end of Cycle 12 was considered to be sufficient length to show 
reliable and lasting treatment effect in terms of PN pain improvement. The rationale for 
randomising approximately 106 participants with an average baseline PAINS-pNF chronic 
target PN pain score ≥3 (documented by daily completion during the screening period) is to 
ensure that sufficient participants are symptomatic for chronic PN pain at study entry; 
therefore, participants have an opportunity to achieve a clinically significant pain severity 
reduction. 
Overall, the study is designed to show both tumour shrinkage and symptom improvement in 
adult participants with symptomatic, inoperable PN. Participants may have a variety of 
PN-related symptoms at baseline including but not limited to PN pain; approximately 
106 participants with a baseline chronic target PN-related pain score of ≥ 3 will be randomised 
to enable analysis of chronic target PN-related pain as a key secondary objective. The 1st key 
secondary endpoint will be tested on participants with a PAINS-pNF chronic target PN pain 
intensity score of ≥ 3 at baseline as these participants have the capacity to show clinically 
meaningful improvement in PN pain.
4.2.1
Participant Input into Design 
Interviews were conducted with a small group of adult patients with NF1 who have 
symptomatic PN to further understand the experience for adult patients with NF1-PN and this 
information was used to help inform the overall study design.
4.3
Justification for Dose
The safety profile of selumetinib has been established in adult patients with advanced cancers 
when given as monotherapy. The maximum tolerated dose of selumetinib in patients with 
advanced cancer is 75 mg bid as hyd-sulfate capsules. Dose escalation of selumetinib was 

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limited principally by the occurrence of rashes and diarrhoea. 
A selumetinib dose of 25 mg/m2 bid was used in the SPRINT study and is the currently 
approved dose in the US for paediatric patients aged 2 years and older. Based on the SPRINT 
study, selumetinib has a flat dose-exposure-response relationship for efficacy and safety across 
the 20 to 30 mg/m2 bid dose range.
In adult healthy subjects, selumetinib exposure was higher in Asian subjects compared to 
non-Asians. Systemic exposure (dose normalised AUC and Cmax) of selumetinib in Chinese 
healthy subjects were a little higher (approximately 1.4-fold) than that in Western subjects. 
However, lower differences were shown when comparing body weight or BSA-normalised PK 
parameters. The geometric mean ratio (90% CI) of the AUC and Cmax, normalised by dose 
and body weight between the Chinese and Western population were 1.19 (1.03, 1.38) and 
1.17 (0.92, 1.48), respectively. Similarly, the differences in mean PK exposure (AUC and 
Cmax) between Japanese and Western subjects were reduced from approximately 1.6 to 
1.8-fold higher to approximately 1.4- to 1.7-fold higher after body weight or BSA 
normalisation.
In population PK analysis, more than race/ethnicity, BSA was identified as the significant 
covariate contributing to selumetinib clearance and volume of distribution. In addition to 
BSA, race (Asian or non-Asian) was correlated to clearance and hence AUC. The clinical 
impact for a typical Asian individual (29-years-old, BSA of 1.8 m2) compared to a typical 
White patient of 10 years old with BSA of 1 m2 was less than 20% for CL. As this is an 
international study with Asian participants, 25 mg/m2 bid (already shown to be efficacious in 
paediatric patients) will provide similar exposure across ethnicities and across the global adult 
population.
Selumetinib, in adult patients with NF1 and inoperable PN, is being evaluated in an ongoing, 
Phase II paired-biopsy study (NCT02407405) sponsored by the NCI. This is an open-label, 
single-arm, single-site study in up to 35 evaluable patients evaluating the efficacy, 
pharmacodynamics, and tolerability of selumetinib. As of the DCO of 21 February 2020, 
27 of 35 planned patients had been enrolled. A 75 mg bid fixed dose was not tolerated; the 
first 2 patients enrolled experienced Grade 3 acneiform rash despite maximum supportive care 
measures; one also developed Grade 3 scalp pain. The dose was reduced to 50 mg bid fixed 
dosing for all patients dosed subsequently. 
Preliminary results show that treatment with selumetinib yields an interim ORR of 50% and 
improved patient reported pain intensity. Treatment resulted in pERK suppression in tumour 
biopsies, consistent with the mechanism of action. Selumetinib was well tolerated with a 
safety profile similar to that already established in paediatric patients with NF1 and adult 
patients with different cancers, and with strong evidence of clinical benefit and objective 
response in adults. Preliminary results from the study were presented at ASCO 2020 

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(O’Sullivan Coyne et al 2020).
In the study described in this CSP, participants will receive selumetinib 25 mg/m2 orally bid 
based on BSA (capped at 50 mg bid when BSA is ≥ 1.9 m2) rather than the 50 mg bid fixed 
dose irrespective of BSA that was used in the adult NF1 NCI study. This individualised BSA 
approach moderates exposure differences amongst ethnic groups. This also aligns with the 
BSA dosing approach used in the paediatric population, where patients continue to be dosed 
according to BSA if they continue treatment into adulthood.
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.
A participant is considered to have completed the study if they have completed all phases of 
the study including the last scheduled visit shown in the SoA. 
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
The end of the study is defined as the date when the last participant has completed their last 
scheduled visit (last participant last visit).
See Section 6.7 for details on participant management following the final DCO as well as 
following study completion.

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4.5
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 SARSCoV-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 AstraZeneca 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, HCP 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 AstraZeneca 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 
minimise 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, 
and guidance on COVID-19 vaccine administration refer to Appendix K.
Note: In Germany the extent of these actions described above is restricted to the COVID-19 
pandemic only; duties overseen by the PI will not be delegated to Health Care Providers 

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(HCP)/Third Party Vendors (TPV) and there will be no verbal consenting. Consent should be 
obtained in written format.
5
STUDY POPULATION
The target population of interest in this study is participants with NF1 who have symptomatic, 
inoperable PN.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Participants who do not meet the eligibility criteria requirements are screen failures; refer to 
Section 5.3.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥ 18 years at the time of screening. 
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 et al 2021): 
(i)
Six or more café-au-lait spots (> 5 mm in greatest diameter in pre-pubertal 
participants or > 15 mm in greatest diameter in post-pubertal participants)
(ii) Freckling in the axillary or inguinal region
- At least one of the two pigmentary findings (café-au-lait macules or freckling) 
should be bilateral
(iii) Two or more iris Lisch nodules identified by slit lamp examination or 2 or more 
choroidal abnormalities—defined as bright, patchy nodules imaged by optical 
coherence tomography/near-infrared reflectance imaging
(iv) Optic pathway glioma
(v) A distinctive osseous lesion such as: sphenoid dysplasia, anterolateral bowing of 
the tibia, or pseudoarthrosis of a long bone
- Sphenoid wing dysplasia is not a separate criterion in case of an ipsilateral 
orbital PN.
(vi) A NF1 heterozygous pathogenic variant with a variant allele fraction of 50% in 
apparently normal tissue such as white blood cells

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(vii)A parent with NF1 by the above criteria
(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 2 or more levels 
with 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 (including significant bleeding or damage to nerves 
and/or surrounding vital structures) 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 caused by the PN, as 
judged by the investigator; symptoms may include, but are not limited to, pain, motor 
dysfunction, and disfigurement.
3
Participants must have completed a pain diary (PAINS-pNF) with a documented chronic 
target PN pain score for at least 4 days out of 7 days for at least 2 weeks during the 
screening period. Participants must have stable chronic PN pain medication use at 
baseline, defined as no clinically significant changes to prescribed chronic PN pain 
medication within 28 days prior to study enrolment or planned at the time of study 
enrolment.
4
Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration 
over the previous 2 weeks prior to baseline or day of first dosing. Participants who are 
wheelchair bound because of paralysis secondary to a PN should be considered 
ambulatory when they are in their wheelchair. Similarly, participants with limited 
mobility secondary to a need for mechanical support (such as an airway PN requiring 
tracheostomy or continuous positive airway pressure) will also be considered ambulatory 
for the purpose of the study.
5
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 measurable by 
volumetric MRI analysis.
6
Adequate organ and marrow function as follows with no blood transfusions (of red blood 
cells/other blood products) within 28 days prior to screening assessment and no growth 
factors within 7 days prior to screening assessment:

Haemoglobin ≥ 9.0 g/dL.

Absolute neutrophil count ≥ 1.5 × 109/L.

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
Platelet count ≥ 100 × 109/L.

Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s 
syndrome (unconjugated hyperbilirubinemia).

Alanine aminotransferase and AST ≤ 2.5 × ULN.

Calculated creatinine clearance ≥60 mL/min as determined by Cockcroft-Gault 
(using actual body weight). 
Males:
CrCL = 
Weight (kg) × (140 – Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
CrCL = 
Weight (kg) × (140 – Age)
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
7
All participants must be able to swallow whole capsules.
Sex
8
Male or female.
Reproduction
9
Negative pregnancy test (serum) for women of childbearing potential.
10 Female participants must be one year post-menopausal, surgically sterile, or using one 
highly effective form of birth control (a highly effective method of contraception is 
defined as one that can achieve a failure rate of less than 1% per year when used 
consistently and correctly). Women of childbearing potential must agree to use one highly 
effective method of birth control. They should have been stable on their chosen method of 
birth control for a minimum of 3 months before entering the study and continue to use it 
throughout the study and until at least one week after the last dose (see Appendix F for 
complete list of highly effective birth control methods). Non-sterilised male partners of a 
woman of childbearing potential must use a male condom plus spermicide (condom alone 
in countries where spermicides are not approved) throughout this period and until at least 
one week after the female participant’s last dose of study intervention. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Total sexual abstinence is an acceptable method provided it is the usual 
lifestyle of the participant.
11 Non-sterilised male participants (including males sterilised by a method other than 
bilateral orchidectomy eg, vasectomy) who intend to be sexually active with a female 
partner of childbearing potential must be using an acceptable method of contraception 

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such as male condom plus spermicide (condom alone in countries where spermicides are 
not approved) (see Appendix F) from the time of screening throughout the total duration 
of the study and the drug washout period (at least one week after the last dose of study 
intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. Vasectomised 
(ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study. Even if the female partner is 
pregnant, male participants should still use a condom plus spermicide (where approved), 
as indicated above during the clinical study. Male participants must not donate or bank 
sperm during this same time period. Female partners (of childbearing potential) of male 
participants must also use a highly effective method of contraception throughout this 
period.
Informed Consent
12 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
13 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of sample for optional genetic research that supports Genomic 
Initiative.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, including uncontrolled hypertension, active bleeding diseases, and 
known moderate or severe hepatic impairment), or history of allogenic organ transplant, 
which, in the investigator’s opinion, makes it undesirable for the participant to participate 
in the study or that would jeopardise compliance with the protocol.
2
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.
3
Participants with confirmed or suspected malignant glioma or MPNST. Participants with 
low grade glioma (including optic glioma) not requiring systemic therapy or radiation 
therapy are permitted.
4
History of malignancy except for malignancy treated with curative intent with no known 
active disease ≥ 5 years before the first dose of study intervention and of low potential 
risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell 
carcinoma of the skin that has undergone potentially curative therapy.

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5
Persistent toxicities (CTCAE Grade ≥ 2) caused by previous therapy for NF1-PN, 
excluding hair changes such as alopecia or hair lightening. Participants with toxicity 
clinically considered to be irreversible (eg, hearing loss) that is not reasonably expected to 
be exacerbated by study intervention may be permitted. 
6
Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface 
antigen or hepatitis B virus core antibody, at screening. Testing is not required for 
assessment of eligibility for the study.
7
Known to have tested positive for HIV. Participants with HIV who have adequate CD4 
count, not requiring antiretroviral medication, may be enrolled. Testing is not required for 
assessment of eligibility for the study.
8
Investigator judgment of one or more of the following:
(a) Mean resting QTcF interval >470 ms, obtained from triplicate ECGs performed at 
screening. 

History of QT prolongation associated with other medications that required 
discontinuation of that medication.

Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives.
9
Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Participants with atrial fibrillation clinically 
well-controlled by medication may be permitted.
10 Participants with clinically significant cardiovascular disease as defined by the following:
(a) Known inherited coronary disease
(b) Acute coronary syndrome within 6 months prior to starting treatment 
(c) Uncontrolled angina – Canadian Cardiovascular Society Grade II to IV despite 
medical therapy (Appendix I) 
(d) Symptomatic heart failure – New York Heart Association Class II to IV
(e) Prior or current cardiomyopathy
(f) Severe valvular heart disease
(g) Baseline LVEF below LLN or < 55% measured by ECHO or cardiac MRI
(h) Uncontrolled hypertension (at screening: BP ≥ 140/90 despite optimal therapy)
11 Participants with the following ophthalmological findings/conditions:
(a) Current or past history of RPED/CSR or RVO
(b) 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. 

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(c) Participants with any other significant abnormality on ophthalmic examination 
should be reviewed for potential eligibility.
(d) 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.
12 Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or 
orthopaedic or dental braces in close proximity to the area of interest that would interfere 
with volumetric analysis of target PN on MRI.
Prior/Concomitant Therapy
13 Prior exposure to MEK inhibitors.
14 Receipt of the last dose of systemic PN target treatment (including chemotherapy, 
immunotherapy, targeted therapy, biologic therapy, or monoclonal antibodies) within 
4 weeks prior to the first dose of study intervention or 5 half-lives of the respective 
systemic PN target treatment, whichever is longer.
15 Has received radiotherapy in the 6 weeks prior to the start of study intervention or any 
prior radiotherapy directed at the target or non-target PN.
16 Major surgical procedure (excluding placement of vascular access) or significant 
traumatic injury within 4 weeks of the first dose of study intervention or an anticipated 
need for major surgery during the study.
17 Receiving herbal supplements or medications at doses known to be strong or moderate 
inducers of CYP3A4 unless such products can be safely discontinued at least 14 days or 
5 half-lives (whichever is longer) before the first dose of study intervention (see 
Appendix J).
18 With the exception of chronic PN pain medication, receiving herbal supplements or 
medications at doses known to be strong or moderate inhibitors of the CYP2C19 and 
CYP3A4 enzymes, unless such products can be safely discontinued at least 14 days or 
5 half-lives (whichever is longer) before the first dose of study intervention (see 
Appendix J). 
19 Any multivitamin containing vitamin E must be stopped at least 7 days prior to initiation 
of study intervention.
Prior/Concurrent Clinical Study Experience
20 Previous treatment in the present study. 
21 Participation in another clinical study with a study intervention or investigational 
medicinal device administered in the last 4 weeks or 5 half-lives, whichever is longer, 
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unless it is an observational (non-interventional) clinical study or during the follow-up 
period of an interventional study.
22 Participants with a known hypersensitivity to selumetinib or any of the excipients of the 
product.
Other Exclusions
23 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
24 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. 
This includes investigator judgement that the participant will not be able to adequately 
understand or consistently complete electronic PRO instruments.
25 Currently pregnant (confirmed with positive pregnancy test), intending to become 
pregnant, or breast feeding (lactation must be discontinued throughout the period of the 
study and until at least one week after the last dose of study intervention). 
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:
1
Participants must follow the contraception requirements outlined in Appendix F.
2
Participants should not donate blood or blood components while participating in this 
study and through 12 weeks after the last dose of study intervention.
Restrictions relating to concomitant therapies are described in Appendix J 2.
5.2.1
Meals and Dietary Restrictions
Study intervention capsules should be swallowed whole with a glassful of water twice a day, 
approximately 12 hours apart (but no less than 6 hours apart), on an empty stomach (no food 
or drink other than water for 2 hours prior to dosing and one hour after dosing).
Participants should refrain from consumption of Seville oranges, grapefruit or grapefruit juice, 
from 7 days before the start of study intervention until after the final dose.
From the end of Cycle 24 (Cycle 25 Day 1) participants will not be required to continue to 
observe the fasting restriction described above, meaning that participant can eat at any time 
point in relation to each selumetinib intake. 
A participant is defined to switch to the fed state from the moment after the end of Cycle 24 
(Cycle 25 Day 1) when the participant is no longer required to continue to observe the fasting 

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restriction and can eat at any time point in relation to each selumetinib intake. The participants 
who reach the end of Cycle 24 prior to the approval of the third protocol amendment will be 
considered in fed state from the timepoint when they will reconsent to participate in the study 
without the fasting restriction and the date of their ICF signature after Cycle 25 Day 1 will be 
the start date of the fed state.
5.2.2
Alcohol
On each PK day, participants will abstain from alcohol for 24 hours before the start of dosing 
until after collection of the final PK sample.
5.2.3
Activity
Participants should be made aware of the need for good oral care during studies with 
selumetinib due to possible risk of oral mucositis and dry mouth (see Appendix H 7 for more 
detail).
5.3
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time if the screening failure was due to a temporary condition. Participants 
who screen fail based on PN pain intensity assessment cannot be rescreened unless it is due to 
a technical reason (ie, e-Diary device not synching with system used to enroll the participant). 
Rescreened participants should be assigned the same participant number (ie, E-code) as for the 
initial screening. Participants should be rescreened once sufficient time has elapsed to feasibly 
allow correction of the reason for screen failure. However, rescreening should be documented 
so that its effect on study results, if any, can be assessed. All assessments must be repeated for 
rescreening unless they are within 28 days of randomisation.
These participants should have the reason for study withdrawal recorded in the eCRF as 
“screen failure” (ie, participant does not meet the required inclusion/exclusion criteria). This 
reason for study withdrawal is only valid for screen failures (ie, participants who are not 
randomised in the study). 
Participant enrolment and randomisation is described in Section 6.3.

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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the CSP.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
AstraZeneca will supply selumetinib and placebo capsules. It will be sent blinded and 
unblinded to the site; blinded label stock will be provided to participants prior to crossover 
and following crossover, unblinded, open label stock will be dispensed to the participant.
Dose modifications are described in Section 6.6.
Table 5
Investigational Products
ARM name
Arm A
Arm B
Intervention 
name
Selumetinib
Placebo
Type 
Drug
Drug
Dose formulation
Capsule
Capsule
Unit dose 
strength(s)
10 mg and 25 mg capsules
Placebo to match selumetinib 10 mg and 
25 mg capsules
Dosage level(s)
25 mg/m2 bid – see BSA dosing table 
below.
Placebo 25 mg/m2 bid – see BSA dosing 
table below.
Route of 
administration
Oral
Oral
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by AstraZeneca
Provided centrally by AstraZeneca
Packaging and 
labelling
Selumetinib 10 mg (white) and 25 mg 
(blue) capsules in 60 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.
Matching placebo (white and blue) 
capsules in 60 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
N/A
bid, twice daily; BSA, body surface area; GCP, Good Clinical Practice; IMP, investigational medicinal product; 
NIMP, non-investigational medicinal product.

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Table 6
Body Surface Area Dosing Guidelines
Body surface area (m2)
Selumetinib starting dose (mg) a
AM
PM
1.1 to 1.29
30
30
1.3 to 1.49
35
35
1.5 to 1.69
40
40
1.7 to 1.89
45
45
≥ 1.90
50
50
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.
Study intervention capsules should be swallowed whole with a glassful of water twice a day, 
approximately 12 hours apart but no less than 6 hours apart, on an empty stomach (no food or 
drink other than water for 2 hours prior to dosing and one hour after dosing). 
From the end of Cycle 24 (Cycle 25 Day 1) participants will not be required to continue to 
observe the fasting restriction described above, meaning that the participant can eat at any 
time point in relation with each selumetinib intake Participants will be therefore considered in 
fed state Refer to Section 5.2.1 for the definition of participant fed state.
If a dose of study treatment is missed, it should only be taken if it is more than 6 hours until 
the next scheduled dose. If vomiting occurs after study treatment administration, an additional 
dose should not be taken. Dosing should be continued with the next scheduled dose.
Selumetinib
Participants in the selumetinib group will receive 25 mg/m2 selumetinib as oral capsules bid. 
Dosing will be based on BSA and capped at 50 mg bid when BSA is ≥ 1.9 m2. 
Placebo
Participants in the placebo group will receive placebo as oral capsules bid. 
Duration of Treatment
Participants in the selumetinib group will receive 25 mg/m2 selumetinib as oral capsules bid 
until a selumetinib discontinuation criterion is met. Participants in the placebo group will 
receive placebo as oral capsules bid until the end of Cycle 12 and then will cross over to 
selumetinib treatment.
Crossover within the study will be permitted. Participants in the placebo group will crossover 
to receive selumetinib after the end of Cycle 12. However, if the investigator requests 

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unblinding due to suspected progression during the randomised period, and the request is 
deemed appropriate, the relevant MRI scans will be assessed by ICR, per REiNS criteria. 
Unblinding will only be permitted if the participant has progression on imaging as determined 
by ICR. If the participant was on placebo they will be allowed to crossover to selumetinib 
treatment. Following crossover to selumetinib treatment, subsequent treatment will be 
open-label.
Participants may continue to receive selumetinib beyond the final DCO as long as they are 
continuing to show clinical benefit, as judged by the investigator, and in the absence of 
discontinuation criteria.
If selumetinib is approved locally and reimbursed for use in adult patients with NF1 who have 
symptomatic, inoperable PN, participants should be switched to the commercial supply at the 
end of the study. However, if the participant is unable to access the commercial supply and 
they are still receiving clinical benefit, AstraZeneca and the Investigator will discuss how the 
participant could continue to receive selumetinib if he/she is benefiting from treatment.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention 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.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in a separate document.
6.3
Measures to Minimise Bias: Randomisation and Blinding
Participant Enrolment and Randomisation
All participants will be centrally assigned to randomised study intervention using IRT. Before 
the study is initiated, login instructions for the IRT and/or login information and instructions 
for the RTSM will be provided to each site.
Study intervention will be dispensed at the study visits summarised in Table 1.

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Returned study intervention should not be re-dispensed to the participants.
If a participant withdraws from the study, then his/her enrolment/randomisation code cannot 
be reused. Withdrawn participants will not be replaced.
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening.
At screening (Days -28 to -1), the investigator or suitably trained delegate will:

Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the participant. 
However, all screening laboratory and imaging results must have been obtained within 
28 days of the first dose of study intervention. 

Participants will be identified to the IRT per country regulations. Obtain a unique 7-digit 
enrolment number (E-code), through the IRT in the following format (ECCNNXXX: CC 
being the country code, NN being the centre number, and XXX being the participant 
enrolment code at the centre). This number is the participant’s unique identifier and is 
used to identify the participant on the eCRFs.

Determine participant eligibility (see Sections 5.1 and 5.2).

Obtain signed informed consent for genetic research study (optional). Participants who 
decide not to sign the specific genetic ICF, but the general study ICF, are eligible for 
study enrolment and all other study procedures.
At randomisation, once the participant is confirmed to be eligible, the investigator or suitably 
trained delegate will:

Assign a randomised treatment group via IRT. Randomisation codes will be assigned 
strictly sequentially within each stratum as participants become eligible for 
randomisation. The system will randomise the eligible participant to one of the 
2 treatment groups. 
If the participant is ineligible and not randomised, the IRT should be accessed to terminate the 
participant in the system.
Participants will begin study intervention on Day 1. Participants must not be randomised and 
treated unless all eligibility criteria have been met.
Procedures for Handling Incorrectly Enrolled or Randomised Participants
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enrolled or receive study medication. 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 
randomised or started on study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on study intervention, 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 study intervention. The AstraZeneca Medical Monitor must ensure all 
decisions are appropriately documented and that the potential benefit/risk profile remains 
positive for the participant.
Methods for Assigning Treatment Groups
The actual treatment given to participants will be determined by the randomisation scheme in 
the IRT. The randomisation scheme will be produced by a computer software programme that 
incorporates a standard procedure for generating randomisation numbers. One randomisation 
list will be produced for each of the randomisation strata. A blocked randomisation will be 
generated, and randomisation will be balanced within the IRT at the central level. 
Randomisation codes will be assigned strictly sequentially, within each stratum, as 
participants become eligible for randomisation. The IRT will provide the kit identification 
number to be allocated to the participant at the randomisation visit and subsequent treatment 
visits. For participants assigned to placebo at randomisation, the cross-over to selumetinib will 
occur after the end of Cycle 12. The switch will be programmed into the IRT system to allow 
the participant to receive selumetinib from that point forward.
Methods for Ensuring Blinding
IRT
The IRT will provide to the investigator(s) or pharmacists the kit identification 
number to be allocated to the participant at the dispensing visit.
Routines for this will be described in the IRT user manual that will be provided to 
each centre.
The randomisation code should not be broken except in medical emergencies when 
the appropriate management of the participant requires knowledge of the study 
intervention randomisation. The investigator documents and reports the action to 
AstraZeneca, without revealing the study intervention given to participant to the 
AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and 
are suspected to be causally related to a study intervention and that potentially 
require expedited reporting to regulatory authorities. Randomisation codes will not 
be broken for the planned analyses of data until all decisions on the evaluability of 
the data from each individual participant have been made and documented.

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Blind break IRT
The IRT will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will 
affect the immediate management of the participant’s condition (eg, antidote 
available), the investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, AstraZeneca must be notified within 
24 hours after breaking the blind. The investigator documents and reports the 
action to AstraZeneca, without revealing the study intervention given to 
participant to the AstraZeneca staff. Emergency unblinding will lead to the 
participant being discontinued from the study following EOT and Safety Follow-
up Visits (see Section 7.2 for procedures for participant withdrawal from study).
The laboratory vendor personnel performing the bioanalysis of the plasma samples 
will have access to the randomisation list.
EOT, end of treatment; IRT, Interactive Response Technology; SAE, serious adverse event.
6.4
Study Intervention Compliance
If participants are dosed at the site (eg, on PK assessment 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. 
Participants will complete a daily drug diary to record whether study intervention was taken as 
instructed.
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Study intervention compliance will be assessed by
review of the daily drug diary, reconciliation of site drug accountability logs and by counting 
returned capsules during each site visit. 
A record of the number of 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. 
Deviation(s) from the prescribed dosage regimen should 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. 

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The investigator(s) is responsible for ensuring that the participant has returned all unused 
study intervention.
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the participant’s safety and wellbeing, 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 
follow-up period following the last dose of study intervention must be recorded in the eCRF 
along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
The AstraZeneca 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.
Strong or moderate inducers of CYP3A4 are not allowed at any time during the study. During 
the first cycle, concomitant use of strong or moderate inhibitors of CYP3A4 or CYP2C19,
with the exception of chronic PN medication, should be avoided until after the PK assessment. 
If concomitant use of selumetinib with strong or moderate CYP3A4 or CYP2C19 inhibitors is 
not avoidable, then the selumetinib dose should be reduced as shown in Appendix J Table J15. 
For chronic PN pain medication fulfilling the above criteria, selumetinib should be initiated at 
a reduced dose as shown in Appendix J Table J15. The dose of selumetinib should be reduced 
for the duration of concomitant therapy with the strong or moderate CYP3A4 or CYP2C19 
inhibitors 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.
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 administered with caution.
Selumetinib capsules contain vitamin E in the form of D-α-tocopheryl polyethylene glycol 

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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 not take any supplemental 
vitamin E. High doses of vitamin E have been reported to cause bleeding and interfere with 
blood coagulation processes. 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.   
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix J 2.
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 H.
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 AEs (Appendix H):
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 7. If the AE does not resolve to CTCAE Grade 1 or less 
within 4 weeks of onset, study intervention must be permanently discontinued unless 
otherwise specified in the Guidance for Management of Specific AEs (Appendix H).
The dose modification procedure is shown in Table 7. 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 7. For example, if a participant has a BSA of 1.8 m2 and 
starts on a dose of 45 mg bid and then has a dose reduction to 35 mg AM, 30 mg PM then a 

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subsequent BSA increase to 1.9 m2 would mean the participant should be dose adjusted to 
35 mg bid. 
Note that if selumetinib is interrupted for more than 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 AstraZeneca 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 AstraZeneca Medical Monitor.
Table 7
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
≥ 1.90
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
Intervention after the End of the Study
As described in Section 4.4, the study will remain open until the last participant has completed 
their last scheduled visit (last participant last visit).
After the final DCO for this study, AstraZeneca will continue to supply selumetinib to 
participants who received selumetinib until disease progression occurs as judged by the 
investigator or until meeting any other discontinuation criteria as defined in Section 7.1. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment with selumetinib may be 
transitioned to such a study, and the current study would 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 proposed to move to such a study would be given a 
new informed consent, as applicable.

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If selumetinib is approved locally and reimbursed for use in adult patients with NF1 who have 
symptomatic, inoperable PN, participants should be switched to the commercial supply at the 
end of the study. However, if the participant is unable to access the commercial supply and 
they are still receiving clinical benefit, AstraZeneca and the Investigator will discuss how the 
participant could continue to receive selumetinib if he/she is benefiting from treatment.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for 30 day safety follow-up. 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:

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 study intervention, 
without prejudice to further treatment. A participant who discontinues study intervention 
is normally expected to continue to participate in the study for the 30 day safety follow-up 
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 or intent to become pregnant.

Initiation of subsequent therapy for NF1-PN, including another investigational agent.

Participants who experience disease progression based on the investigator’s decision.

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Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
Crossover within the study will be permitted (see Section 6.1.1 for details).
See the SoA (Table 1) for data to be collected at the time of intervention discontinuation 
(ie, the EoT visit) and follow-up and for any further evaluations that need to be completed.
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention
All participants who discontinue the study intervention will be followed up for safety 
assessments 30 days after their last dose of study intervention. Additional assessments to be 
performed at the time of the 30 day safety follow-up are detailed in the SoA (Table 1). 
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. Emergency unblinding will also lead to the 
participant being discontinued from the study following EOT and Safety Follow-up 
Visits. 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 EoT visit should be conducted, 
as shown in the SoA. See SoA (Table 1) 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 the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, AstraZeneca 
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 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.

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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 no contact has been established by the time the study is completed 
(see Section 4.4).
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 protocol.
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 the participant 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 have been 
lost to follow-up from the study.
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 (Table 1 and Table 2). Data 
collection following study analysis until the end of the study is described below. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

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
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) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Data Collection Following Study Analysis until the End of the Study
Following the DCO2 for the primary efficacy endpoint, participants will continue with all 
assessments as indicated in the SoA. 
For SAE and AE reporting and laboratory assessment collection after final analysis, see 
Section 8.3.11.
After the final DCO and database closure, only SAEs will be reported for the purposes of this 
study (see Section 8.3.11).
8.1
Efficacy Assessments
8.1.1
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 other MRI analysis techniques. MRI with volumetric analysis is 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. Prior to starting treatment on this study, the investigator must 
select a single target PN. The target PN is defined as the clinically most relevant PN, 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. Non-target PNs must also be measurable. AstraZeneca’s appointed imaging 
CRO will measure the target PN and non-target PN (if applicable). However, the management 
of participants will be based upon the results of the PN assessments conducted by the 
investigator using their standard of care methods.

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The MRI Images, including unscheduled visit scans, will be collected on an ongoing basis and 
sent to an AstraZeneca-appointed imaging CRO for QC, 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 independent central 
review of images will be performed for the assessment of efficacy according to the REiNS 
criteria. In general, 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. However, if the investigator requests unblinding due to suspected progression 
during the randomised period, and the request is deemed appropriate, the relevant MRI scans 
will be assessed by ICR per REiNS criteria. Unblinding will only be permitted if the 
participant has progression on imaging as determined by ICR. If the participant was on 
placebo they will be allowed to crossover to selumetinib treatment.
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 1, 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 24 cycles. From the end of Cycle 24, tumour assessments will be 
performed every 6 cycles (24 ± 1 weeks), as long as the participant remains on study 
intervention. Volumetric MRI assessment of the target and non-target PNs according to the 
REiNS criteria will be performed by the central imaging vendor. If an unscheduled assessment 
is performed (eg, to investigate clinical signs/symptoms of progression) and the participant 
has not progressed, the subsequent assessments at the next scheduled visit must be performed.
The REiNS criteria as assessed by volumetric MRI of the target PN performed by the ICR are 
as follows:

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.

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
Partial response: decrease in the volume of the target PN by 20% or more compared to 
baseline. The PR 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 PR 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. 
Before submitting the MRI scans to the central review vendor site staff should ensure that the 
target PN and non-target PN (if applicable) are fully visible on the scans.
In the event that a participant taking part in the study had a target PN resection and remained 
in the study, MRI scans will continue to be collected.
8.1.2
Independent Central Review of Scans
Independent central review of scans will be conducted as described in Section 8.1.1. A double 
read of all MRI scans will be performed. The ICR reviewers will be blinded to study 
intervention group. 
8.1.3
Objective Response Rate
Objective response rate is defined as the proportion of participants 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 PR (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.
8.1.4
Progression Free Survival
Progression free survival is defined as the time from the date of first selumetinib dose until 
date of progression by ICR per REiNS criteria or death (due to any cause). 
8.1.5
Duration of Response
Duration of response will be defined as the time from the date of first documented response 
(which is subsequently confirmed) until date of documented progression by ICR per REiNS 

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criteria or death due to any cause. 
8.1.6
Time to Progression
Time to progression is defined as the time from the date of first selumetinib dose until date of 
documented objective disease progression by ICR per REiNS criteria. 
8.1.7
Time to Response
Time to response is defined as the time from date of first selumetinib dose until the date of 
first documented objective response (which is subsequently confirmed), by ICR per REiNS 
criteria. 
8.1.8
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. Clinical outcome 
assessments can be reported by a participant (PRO), a clinician (ClinRO), an observer 
(ObsRO), 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 
health-related QoL of the participant to aid understanding of the risk-benefit profile.
A PRO is one type of COA and is a general term referring to all outcomes and symptoms that 
are directly reported by the participant. Patient reported outcomes have become important in 
evaluating the effectiveness of study interventions in clinical studies and will aid in 
understanding of the benefit/risk evaluation (EMA Guideline 2016, 
FDA Guidance for Industry). 
The following PRO instruments will be administered in this study: 

Pain Intensity Plexiform Neurofibroma (PAINS-pNF)

Pain Interference Index Plexiform Neurofibroma (PII-pNF)

Patient reported Outcomes Measurement Information System (PROMIS physical function 
items)

Plexiform Neurofibromas Quality of Life Measure (PlexiQoL)

Paediatric Quality of Life Inventory (NF1 module acute Version 3.0 – adult report) Skin 
Sensations domain

EuroQol 5-Dimension 5-level (EQ-5D-5L)

Patients Global Impression of Change (PGIC)

Patients GLOBAL Impression of Severity (PGIS)

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Patient Reported Outcomes will be administered according to the SoA.
The ECOG performance status will also be assessed as a COA in this study.
Patient reported outcomes data collection will be discontinued after the participant 
discontinues study intervention.
8.1.8.1
PAINS-pNF 
The use of an NRS-11 measure is well established for measuring pain intensity 
(Atkinson et al 2010; Dworkin et al 2005; Wolters et al 2013; Wolters et al 2016). Pain 
intensity is considered a core concept that is important to assess in the NF1 population 
(Wolters et al 2013). The REiNS International Collaboration, after assessing PRO measures 
for pain in patients with NF1, recommended the NRS–11 for use in the assessment of pain 
intensity in patients aged ≥8 years (Wolters et al 2016). This measure was found to be both 
reliable and valid, and it is preferred over other measures such as the Visual Analogue Scale 
and the Faces Pain Scale-Revised because of its psychometric properties and wide use in 
clinical research (Wolters et al 2013). However, there is no NRS-11 measure specifically 
validated for patients with NF1-PN. To address this gap, the NCI is currently going through 
the qualification process with the PAINS-pNF Scale (FDA Drug Development Tool). The NCI 
is willing for its qualitative work to be used in support of the PAINS-pNF measure to be used 
in the proposed Phase III study in adult NF1-PN participants.
For this study, the PAINS-pNF which is a ‘fit for purpose’ measure for NF1-PN patients that is 
based on an NRS-11 scale will be used. The PAINS-pNF has 2 items, one assessing 
participants’ experience of spikes of PN-related pain intensity (also known as episodic tumour 
pain), which are defined as sudden bursts of tumour pain that may occur spontaneously or in 
response to a stimulus and the other item is their experience of chronic PN-related pain 
intensity (also known as usual tumour pain), which is defined as tumour pain that is present 
most of the time, both for a target PN-location. Participants report pain intensity by selecting 
the number/integer from 0 (no tumour pain [spike]/no tumour pain [usual/chronic]) to 10 
(worst tumour pain possible [spike]/worst tumour pain possible [usual/chronic]). In the event 
that a participant taking part in the study had a target PN resection and remained in the study, 
PAINS-pNF data will continue to be collected.
A copy of the scale is provided in Appendix G 1.
8.1.8.2
PII-pNF
The PII-pNF assesses the extent to which PN pain interferes with daily functioning. All items 
ask the participant to consider the pain related to their PN in the past 7 days. Participants are 
asked how much their PN pain has made it hard for them to engage in physical activities 
(eg, challenging physical activities, self-care), affected their physiological processes 
(eg, sleep, energy) or impacted their social-emotional functioning (eg, enjoyment of activities, 

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mood). Items are rated on a 7-point Likert scale (0 = not at all to 6 = completely), and the total 
score is the mean of the completed items. 
A copy of the scale is provided in Appendix G 2
8.1.8.3
Pain Medication Assessment Diary
Pain Medication e-Diary
At the screening visit, the site staff will pre-populate the e-Diary on the handheld device with 
the pain medications that the participant uses for chronic PN pain, as well as any medications 
that they typically use for spikes of PN pain.
On a daily basis the participant will record on the e-Diary the pain medications that they have 
taken for their chronic PN pain and spikes of PN pain.
The participant should bring their handheld device to each site visit; the site staff will review 
if any changes need to be made to the pre-populated medications on the device.
Investigator Assessment of Pain Medication
At the frequency stipulated in the SoA, the investigator will record in the eCRF if the 
participant’s analgesic requirement has changed compared to baseline since it was last 
assessed. This assessment will be made based on discussions with the participant and 
knowledge of any changes in their pain management. If the investigator determines that there 
has been a change, they will record if there has been an increase or decrease and the reason for 
this change.
8.1.8.4
PROMIS
The Adult PROMIS Physical Functioning (PF) items scales measure self-reported capability 
rather than actual performance of physical activities. Items assess upper extremity function 
(dexterity), lower extremity function (walking or mobility), and central regions (neck, back) as 
well as activities of daily living such as running errands. 
Participants will be assessed using selected items from the PROMIS item bank that map to 
physical function concepts relevant to patients with symptomatic PNs. 
A copy of the scale is provided in Appendix G 3.
8.1.8.5
PlexiQoL
The PlexiQoL is a patient-derived QoL measure specific to adults with NF1-associated PNs. It 
assesses the impact of PNs on patients’ ability to fulfil their human needs. The scale adopts 
the needs -based model of QoL and joins a large portfolio of high-quality outcome measures 
that are widely used in international clinical trials (Heaney et al 2020). 

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The measure consists of 18 dichotomous items with 0 =”Not True” and 1 = “True”. Scores are 
summed to a maximum of 18, with lower scores indicating better quality of life. 
A copy of the scale is provided in Appendix G 4.
8.1.8.6
PedsQL (NF1 Module Acute Version 3.0 – Adult Report) Skin Sensations 
Domain
The adult version of PedsQL™ NF1 Module can be used to understand the multidimensional 
nature of NF1 on the HRQoL patients with this disorder and may assist in medical decision 
making. The instrument demonstrates initial feasibility, reliability, and discriminant validity. 
The PedsQL™ NF1 Module 3.0: Adult self-report instrument comprises 18 domains/subscales 
and participants will be assessed using the Skin Sensations domain (3 items) with a 7-day 
recall period (Nutakki et al 2013).
These are rated on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Items are 
reversed scored and linearly transformed to a 0 to 100 scale as follows: 0 = 100, 1 = 75, 
2 = 50, 3 = 25, 4 = 0. Domain scores are calculated by the sum of all the items over the 
number of items answered.
A copy of the scale is provided in Appendix G 5.
8.1.8.7
PGIC and PGIS
The global impressions of change for PN-related pain are self-reported measures that will be 
used to assess change in participant’s PN-related pain as follows:

PGIC 1: ‘since your last visit to the study site’

PGIC 2 ‘since starting the study medication’
The 2 PGICs will be used to evaluate the clinical significance of changes in PN-related spikes 
of pain and chronic pain on a 7-point scale (1 = Very much improved to 7 = Very much worse) 
(Guy 1976). 
The global impression of severity for PN-related pain is a self-reported measure used to assess 
severity of participant’s PN-related pain. It is a global two-item measure and will be used to 
evaluate the clinical significance of PN-related spikes of pain and chronic pain severity on a 
4-point scale (1 = No pain to 4 = Severe).
Copies of the scales are provided in Appendix G 6 (PGIC) and Appendix G 7 (PGIS).
8.1.8.8
EQ-5D-5L
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility.

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The EQ-5D-5L, developed by the EuroQoL Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (EuroQol 2019). The EQ-5D-5L questionnaire comprises 6 questions that cover 
5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) over 5 levels of increasing severity (“no problems,” “slight problems,” 
“moderate problems”, “severe problems”, and “extreme problems”). Participants indicate their 
current health state by selecting the most appropriate level in each of the 5 dimensions. 
Respondents also assess their health today using the EQ-VAS, which ranges from 0 (worst 
imaginable health) to 100 (best imaginable health).
A copy of the scale is provided in Appendix G 8.
8.1.8.9
Administration of ePRO Questionnaires
Participants will complete a daily e-Diary using a hand-held device at home to capture: 

PN pain intensity (assessed using the PAINS-pNF)

PN pain medication use

Drug diary to record whether study intervention was taken as instructed 
For all other ePRO assessments including PII-pNF, PGIC, PGIS, PROMIS physical function 
items, PlexiQol, Peds QL (NF1 module-adult form) Skin Sensations domain, and EQ-5D-5L, 
participants will perform the ePRO assessments using an electronic tablet during clinic visits 
at the time points indicated in the SoA.
Each site must allocate the responsibility for the administration of the ePRO 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 PRO data via an electronic device:

The PRO questionnaires should be completed prior to any other study procedures or 
discussions (following informed consent) that could bias the participant’s responses to the 
questions.

At site visits, when each instrument is due to be completed, the following order should be 
observed: 

Patient Global Impression of Severity (PGIS)

Patient Global Impression of Change (PGIC)

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
Patient reported Outcomes Measurement Information System (PROMIS physical 
function items)

Paediatric Quality of Life Inventory (PedsQL NF1 module acute Version 3.0 – adult 
report) Skin Sensations domain

Plexiform Neurofibromas Quality of Life Measure (PlexiQoL)

EuroQol 5-Dimension 5-level (EQ-5D-5L)

The PRO questionnaires should be completed by the participant in a quiet and private 
location.

The participant should be given sufficient time to complete the PRO questionnaires at 
his/her own speed.

The research nurse or appointed site staff should explain to participants 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, 
he/she should discuss them with the doctor or research nurse separately from the ePRO 
assessment.

The research nurse or appointed site staff must train the participant on how to use the 
ePRO 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 participant is completing the ePRO at home.

All questionnaires must be completed using the ePRO device. Paper questionnaires may 
be allowed in this study under exceptional circumstances (eg, an IT system failure or 
breakage of electronic device).

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.

The participant should not, wherever possible, receive help from relatives, friends, or 
clinic staff to read or complete the ePRO questionnaires. However, if the participant has 
motor or reading difficulties that will prevent them from using the e-Device, the items 
may be read aloud or responses selected on the e-Device. Any person providing 
assistance must be informed by site staff that they must not influence the participant’s 
responses in any way and responses selected on the e-Device on behalf of the participant 
must follow the answer provided by the participant aloud.

Site staff must administer 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.

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
It is vital that the ePRO reporting is initiated as specified in the SoA to capture the effect 
of study intervention.

Reminders should be sent to participants at home as needed to ensure compliance with the 
assessment schedules.

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 participant could not 
complete assessments, in the source documents and in the designated eCRF. If a 
participant’s 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 participant to improve compliance, a check in call from the site to ask 
the participant if they have any difficulties in completing questionnaires on schedule, etc). 
Whilst site staff will be able to monitor compliance they will remain blinded to the 
PAINS-pNF scores (except in exceptional circumstances when paper copies are used).

In the event that the ePRO device cannot be used (ie, technical failure, lost device, etc) 
and there is a back-up platform available for the PRO questionnaire, the participant will 
complete it on a website following the same steps as outlined above.
8.1.8.10
Qualitative Participant Interviews
Qualitative interviews will be performed in approximately 36 trial participants at baseline and 
at 2 other timepoints during the trial. During the baseline interviews, trial participants will be 
asked a series of questions to better understand their experience with PN symptoms and any 
associated impacts. Interviews over the course of the trial will focus on any changes to 
experienced PN symptoms and impacts. A semi-structured interview guide will be provided in 
the separate interview study manual. These interviews will be conducted by trained 
independent moderators in selected countries. Participation in these interviews is optional, and 
subjects must indicate willingness to participate in the informed consent form. The interview 
results will be reported separately from the clinical study report.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations

A full 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, musculoskeletal (including spine and 
extremities), urogenital, dermatological, gastrointestinal, endocrine, 
haematologic/lymphatic, and neurological systems.

Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology. A targeted physical examination will include, at a 

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minimum, assessments of the general appearance, respiratory and cardiovascular systems, 
skin and abdomen (liver and spleen). 
Physical examination, as well as assessment of height and weight, will be performed at 
timepoints 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 8.3.5 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.
8.2.2
Height and Weight
Height and weight will be measured at the timepoints 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.
Height: The participants should take off shoes and heels should be placed against a wall with 
ankles together. Height should be measured in a standing position with a stadiometer. 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: 

Mosteller: √ (weight (kg) × height (cm) / 3600)
8.2.3
Vital Signs
Vital signs will be performed at timepoints as specified in the SoA.
Temperature, (same method to be used throughout the study), 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). The average 
of 3 BP readings, taken consecutively at intervals of at least one minute apart will be recorded 
in the eCRF.

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Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. 
8.2.4
Electrocardiograms
Single 12-lead ECGs will be performed at timepoints as specified in the SoA after the 
participant has been resting semi-supine for at least 5 minutes and recorded while the 
participant remains in that position using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QT interval corrected by Fridericia’s formula 
(QTcF) intervals. 
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities in QTc interval detected require triplicate 
ECG results. At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained in succession, no more than 2 minutes apart. The full set of 
triplicates should be completed within 5 minutes.
Single ECGs should be performed at the time of significant LVEF drop 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.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
8.2.5
Echocardiogram/Cardiac MRI
An ECHO or cardiac MRI scan to assess LVEF will be performed at the visits as shown in 
SoA. The modality of the cardiac function assessments must be consistent for a given 
participant (ie, if ECHO is used for the screening assessment for a given participant, then 
ECHO should also be used for subsequent scans for that participant). The participants should 
also be examined using the same machine and operator whenever possible, and quantitative 
measurements should be taken (ie, 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 or cardiac MRI assessment. 
Participants experiencing an asymptomatic LVEF reduction or left ventricular systolic 
dysfunction should be managed according to the algorithm provided in Appendix H 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 a follow-up 
ECHO or cardiac MRI, ECG, vital signs, and weight performed after 30 days to evaluate the 
potential for reversibility.

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An ECHO or cardiac MRI 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 or cardiac MRI 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/cardiac MRI scan performed within 4 weeks prior to study 
intervention discontinuation, the discontinuation visit ECHO/cardiac MRI scan is not required 
unless clinically indicated. 
Situations in which ECHO/cardiac MRI scan results should be reported as AEs are described 
in Section 8.3.5.
8.2.6
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.
Urine microscopy will be assessed if other urinalysis measurements are abnormal or if 
clinically indicated.
Other safety laboratory tests include assessment for pregnancy for women of child-bearing 
potential. A serum pregnancy test is required at screening, following that a urine or serum 
pregnancy test is acceptable. Pregnancy tests will be performed every cycle throughout the 
entire exposure period. Pregnancy tests may be performed at the site using a licensed test 
(urine or serum pregnancy test). Where a pregnancy test is the only assessment for a cycle, a 
clinic visit is not required as the test may be performed offsite. The site should obtain the test 
result from the participant prior to the next onsite visit. Abnormal clinically significant 
laboratory results should be repeated as soon as possible (preferably within 24 to 48 hours). 
The following laboratory variables will be measured.

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Table 8
Laboratory Safety Variables
Haematology/haemostasis (whole blood)
Clinical chemistry (serum or plasma)
Haemoglobin
Creatinine a
Leukocyte count
Bilirubin, total
Leukocyte differential count (absolute count) b
Alkaline phosphatase
Platelet count
AST
Absolute neutrophil count
ALT
Absolute lymphocyte count
Albumin
Total white blood cell count
Potassium
Total red blood cell count
Calcium, total
Sodium
Creatine kinase c
Amylase 
Magnesium
Urinalysis d
Gamma-glutamyl transferase
Haemoglobin/Erythrocytes/Blood 
Protein, total
Protein/Albumin 
Urea /blood urea nitrogen g
Glucose 
Coagulation variables (aPTT, PTT, and INR) e
Phosphate
Troponin f
a
Creatinine clearance and glomerular filtration rate to be calculated at screening and if clinically indicated.
b
If absolute count is unavailable per site practice, % /ratio can be entered.
c
Creatine kinase to be assessed in accordance with the schedule of activities and if unexplained muscle weakness or 
myalgia (muscle pain) occurs see Section 8.2.1 for additional information.
d
Urine microscopy will be assessed if other urinalysis measurements are abnormal or if clinically indicated.
e
Coagulation variables to be assessed at screening and if clinically indicated. If both aPTT and PTT tests are not 
performed per local laboratory it is acceptable to enter the results for the test which is performed and leave the other test
result as blank/ not done. If INR is not available per site practice, Prothrombin time can be entered.
f
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 H.
g
Urea or blood urea nitrogen based on local site practice.
ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; 
CK MB, creatine kinase-myocardial band; INR, international normalised ratio; LLN, lower limit of normal; LVEF, left 
ventricular ejection fraction PTT, partial thromboplastin time.
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. 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 8.3.5.

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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.
NB. In case a participant shows an AST or ALT ≥ 3× ULN together with TBL ≥ 2 × ULN 
please refer to Appendix E “Actions required in cases of increases in liver biochemistry and 
evaluation of HL”, for further instructions. 
8.2.7
Ophthalmologic Examinations
An ophthalmologic examination (best corrected visual acuity, IOP and slit-lamp 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 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 
according to Appendix H. 
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. 
8.2.8
Other Safety Assessments
8.2.8.1
ECOG Performance Status
ECOG performance status will be assessed at the times specified in the SoA based on the 
following:
0
Fully active; able to carry out all usual activities without restrictions.
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work).
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair.
5
Dead

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Any significant change from baseline or screening must be reported as an AE.
8.3
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, recording, and 
reporting events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected from the time of signature of the ICF, throughout 
the treatment period and until the follow-up period is completed. Collection and reporting of 
AEs and SAEs after the final DCO is described in Section 8.3.11.
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention 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 AstraZeneca.
8.3.2
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.
Adverse Event Variables
The following variables will be collected for each AE:

AE (verbatim).

The date when the AE started and stopped.

The CTCAE grade and changes in CTCAE grade.

Whether the AE is serious or not (Appendix B).

Investigator causality rating against the study intervention(s) (yes or no).

Action taken with regard to study intervention(s).

AE caused participant’s withdrawal from study (yes or no).

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
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.

Seriousness criteria.

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 National Cancer Institute 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).
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention 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 implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: “Have you 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 

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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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
and ECHO/cardiac MRI scans will be summarised in the Clinical Study Report.
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs, 
physical examinations, ophthalmologic examinations, ECGs and ECHO/cardiac MRI should 
therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason for 
discontinuation of treatment with the study intervention 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 study intervention interruption).
If deterioration in a laboratory value/vital sign/ECG/ECHO or cardiac MRI 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 or cardiac MRI 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 PD, 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.
8.3.6 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 E for further instruction on cases of 
increases in liver biochemistry and evaluation of HL. 
8.3.7 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 

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development of new symptoms, or the progression of existing symptoms, of NF1-PN should 
be considered as PD and not an AE. Events, which are unequivocally due to PD, should not be
reported as an AE during the study.
8.3.8 Disease Under Study
Symptoms of the 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.
8.3.9
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

An AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Statement of Death page in the eCRF. The report should assign the 
main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study intervention, then it should also 
be reported as an SAE.
Note: In Germany SAE reporting has to be done immediately without undue delay after 
obtaining knowledge.
8.3.10
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of selumetinib safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI can be serious or non-serious. 
All AESIs 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 8.3.12. Adverse 
events of special interest based on examinations and tests should be reported in accordance 

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with Section 8.3.5. Adverse events of special interest are shown in Table 9.
Table 9
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.
AESI, adverse event of special interest; MedDRA, Medical Dictionary for Regulatory Activities. 
8.3.11
Safety Data to be Collected Following the Final DCO of the Study
For participants continuing to receive selumetinib after the final DCO, AEs and SAEs will be 
collected, but only SAEs will be reported. In addition, it is recommended that investigators 
monitor the participant’s safety laboratory results periodically during treatment with 
selumetinib in order to manage AEs, consistent with the dose modification guidelines for 
management of study intervention-related toxicities (see Section 6.6). All data after the final 
DCO and database closure will be recorded in the participant notes but, with the exception of 
SAEs, will not otherwise be reported for the purposes of this study.
All SAEs that occur in participants still receiving selumetinib (or within the 30 days following 
the last dose of selumetinib after the final DCO must be reported as detailed in Section 8.3.12. 
8.3.12
Reporting of Serious Adverse Events
All SAEs have to 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, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 

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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 is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it. Note: In Germany SAE reporting has to be done immediately without undue delay after 
obtaining knowledge.
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 IB for selumetinib.
8.3.13
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca.
8.3.13.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, selumetinib should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day, ie, immediately but no 

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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 SAEs (see Section 8.3.12) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.3.13.2
Paternal Exposure
Non-sterilised male participants who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
the duration of the study (from the time of screening) and for 7 days after the last dose of 
study intervention. 
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) occurring from the date of the first dose of study intervention 
until 7 days after the last dose of study intervention should be followed up and documented in 
the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 
from the partner must be obtained before the information is collected and reported to 
AstraZeneca.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRBs/IECs prior to use.
8.3.14
Medication Error, Drug Abuse, and Drug Misuse
8.3.14.1
Timelines
If a medication error, drug abuse, or drug misuse occurs in the course of the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one day, ie, immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 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 8.3.12) and 
within 30 days for all other events.

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Note: In Germany SAE reporting has to be done immediately without undue delay after 
obtaining knowledge.
8.3.14.2
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.
8.3.14.3
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.
8.3.14.4
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.
8.3.15
Medical Device Deficiencies
This section is not applicable.
8.4
Overdose
Use of selumetinib in doses exceeding that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of selumetinib and 
possible symptoms of overdose are not established. 

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 inform appropriate AstraZeneca representatives 

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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 8.3.12) and within 30
days for all other overdoses.
Note: In Germany SAE reporting has to be done immediately without undue delay after 
obtaining knowledge.
8.5
Human Biological Samples
Instructions for the collection, handling, storage and shipping 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. 

Remaining unused PK samples may be used for exploratory biomarker analysis as 
indicated in Section 8.6.2 and is subject to agreement in the ICF.

Samples will be stored for a maximum of 15 years from the date of the issue of the 
clinical study report in line with consent and local requirements, after which they will 
be destroyed/repatriated.

Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, individual or pooled samples to 
further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the clinical study report.

Samples collected in China will be stored and disposed of according to local laws and 
regulations. PK samples collected in China will be destroyed after finalisation of 
Bioanalytical Report or completion of clinical study report.
For further details on Handling of Human Biological Samples, see Appendix C. 
8.5.1
Pharmacokinetics

Blood samples will be collected for measurement of plasma concentrations of selumetinib 
and N-desmethyl selumetinib as specified in the SoA.

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and AstraZeneca, eg, for safety reasons. The timing 
of sampling 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. 

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
Plasma samples will be used to analyse the PK of selumetinib and N-desmethyl 
selumetinib. Samples collected for analyses of 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 by a bioanalytical laboratory. Samples will be
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Collection of Samples
Blood samples will be collected for measurement of selumetinib and N-desmethyl selumetinib 
as shown in Table 10. The selumetinib dose dates and times must be recorded accurately on 
the day preceding the PK sample day and on the PK sample day.
Table 10
Pharmacokinetic Sampling Schedule
Pre-Dose a
0.5 hour b
1.5 hour b
3 hour b
6 hour b
8 hour c
Cycle 1 Day 8 
(Day 4 to Day 14) d
X
X
X
X
X
X
a
Within 10 minutes prior to dosing.
b
Time allowance ± 10 minutes. 
c
Time allowance ± 15 minutes. The second dose of selumetinib should be taken after the 8 hour sample
d
Pharmacokinetic sampling is targeted for Day 8, however for operational reasons the PK sampling can take 
place on any day between Day 4 and Day 14 as long as the participant has received 3 consecutive days of 
dosing immediately prior to the PK day. Every effort should be made to conduct PK sampling within the 
Day 4 – Day 14 window. However, if for unforeseen reasons this is not possible, PK sampling can be 
performed at any day prior to the end of Cycle 12 provided the participant has received 3 consecutive days 
of dosing immediately prior to the PK day.
PK, pharmacokinetics.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or 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.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
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.
Samples from participants assigned to placebo will only be analysed if there is cause to expect 
incorrect study drug administration.

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8.5.2
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study. 
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Mandatory biomarker samples will not be collected in this study. 
8.6.2
Other Study-related Biomarker Research

Already collected PK samples may be analysed to explore potential biomarkers, which 
may influence the progression of neurofibromatosis and inoperable plexiform 
neurofibromas (and associated clinical characteristics) and/or identify participants likely 
to respond to selumetinib, or may be surrogate markers of response. Exploratory 
biomarker analysis may include (but is not limited to) pERK, cytokines, and/or 
quantification of RNA expression using quantitative RT-PCR, microarray or other 
technology in blood, PBMCs, serum, or plasma to evaluate their association with 
observed responses to selumetinib.

Other study-related biomarker research excludes genomic analysis, but targeted sequence 
analysis on genes involved in neurofibromatosis might be included.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum. 
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. See Appendix D for information regarding the storage and destruction of genomics 
initiative genetic sample. Details on processes for collection and shipment and destruction of 
these samples can be found either in the appendices or in the Laboratory Manual. 
Note: This sample will not be collected in China and will only be collected in other countries 
where locally applicable/permissible.
8.8
Medical Resource Utilisation and Health Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are not 
evaluated in this study.

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9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives. 
A comprehensive SAP will be prepared 90 days post FSI with final amendments completed 
prior to DBL for DCO1.
The SAP will be signed off before review of any potential treatment-revealing data is 
undertaken (this includes blinded delivery reviews). For all situations, a full draft of the SAP 
should be available to ensure sufficient time to prepare for any blinded or unblinded data 
review.
9.1
Statistical Hypotheses
The hypothesis of interest with regards to the primary efficacy endpoint is:

H0: ORRselumetinib = ORRplacebo

H1: ORRselumetinib ≠ ORRplacebo
Where ORR is assessed by landmark end of Cycle 16.
The hypothesis of interest with regards to the 1st key secondary endpoint is:

H0: μPain, selumetinib – μPain, placebo = 0

H1: μPain, selumetinib – μPain, placebo ≠ 0
Where μPain represents the mean change from baseline in PAINS-pNF chronic target PN pain 
intensity score at Cycle 12. 
The hypothesis of interest with regards to the 2nd key secondary endpoint is:

H0: μQoL, selumetinib – μQoL, placebo = 0

H1: μQoL, selumetinib – μQoL, placebo ≠ 0
Where μQoL represents the mean change from baseline in PlexiQOL total score at Cycle 12. 
The MTP will define which significance levels should be applied to the interpretation of the 
raw p-values for the primary endpoint (ORR by end of Cycle 16), the 1st key secondary 
endpoint (change from baseline in PAINS-pNF chronic target PN pain intensity score at Cycle 
12) and the 2nd key secondary endpoint (change from baseline in PlexiQOL total score at 
Cycle 12) intended for label claims as described in Figure 3 and will be further detailed in the 
SAP.
To preserve the overall type 1 error (familywise error rate) at 5% (two-sided) in the strong 

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sense, the MTP will be implemented for each endpoint in order at the interim analysis (DCO1, 
if performed) and if required at the primary analysis (DCO2).
Figure 3
Multiple Testing Procedure
DCO, data cut off; FAS, Full analysis set; H0, null hypothesis; ORR, Objective response rate; PAINS-pNF, PAin 
INtensity Scale for plexiform neurofibromas; PlexiQOL, Plexiform Neurofibroma Quality of Life scale; PN, 
plexiform neurofibromas.
Significance levels will be adjusted for each confirmatory endpoint in order to preserve the 
overall type 1 error (familywise error rate) at 5% (two-sided) in the strong sense by defining a 
gatekeeping strategy where the families of hypotheses are tested in a sequential manner. Each 
family will be defined by one endpoint and the two associated tests (DCO1 and DCO2): first 
family based on the primary endpoint, second family based on the 1st key secondary endpoint 
and the third family based on the 2nd key secondary endpoint. All alpha 0.05 (two-sided) will 
be initially assigned to the primary endpoint. If statistical significance for the primary 
endpoint is reached (either at DCO1 or at DCO2), the overall alpha 0.05 (two-sided) will be 
sequentially re-assigned to test the 1st key secondary endpoint. If statistical significance is 
reached for the 1st key secondary endpoint, then the overall alpha 0.05 (two-sided) will be 
sequentially re-assigned to test the 2nd key secondary endpoint. If statistically significance is 
not reached for the primary endpoint, the p-value of the key secondary endpoints will be only 
nominal. If statistically significance is not reached for the 1st key secondary endpoint either at 
DCO1 or at DCO2, the p-value of the 2nd key secondary endpoint will be only nominal. 
The interim analysis (i.e., when the 100th randomised patient has had the opportunity to have 

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their end of cycle 16 assessment) will take place with approximately 68.5% of the primary 
endpoint information expected at the primary analysis. For the first family, a split alpha 
strategy will be conducted where an alpha of 0.003 (two-sided) will be initially allocated to 
test at DCO1. If statistical significance is not reached at DCO1, the primary endpoint will be 
tested again at DCO2 with the remaining alpha of 0.047 (two-sided). If statistical significance 
of the primary endpoint is reached at DCO1 or DCO2, the overall alpha of 0.05 (two-sided) 
will be allocated to the 1st key secondary endpoint. Similarly, if statistical significance of the 
1st key secondary endpoint is reached at DCO1 or DCO2, the overall alpha of 0.05 (two-
sided) will be allocated to the 2nd key secondary endpoint. For the second and third families, 
the Haybittle-Peto approach will be applied within the family. 
For the 2nd family, the expected information fraction (IF) at DCO1 is 95.2% and an alpha of 
0.02 (two-sided) will be allocated to the DCO1 test (if statistical significance of the primary 
endpoint is reached at DCO1) and an alpha of 0.049647668 (two-sided) will be assigned to 
DCO2, if non-statistical significance is reached DCO1 and test needs to be repeated at DCO2. 
Similarly for the 3rd family, the IF at DCO1 is expected to be 94.8% and an alpha of 0.02 
(two-sided) will be allocated to the DCO1 test (if statistical significance of the 1st key 
secondary endpoint is reached at DCO1) and an alpha of 0.049566079 (two-sided) will be 
assigned to DCO2, if non-statistical significance is reached DCO1 and test needs to be 
repeated at DCO2.
The actual IF for each key secondary endpoint will be calculated at the time of the analysis 
and adjustments to the alpha will be made accordingly. If the IF is observed to be 100% at 
DCO1, then the overall alpha of 0.05 (two-sided) will be available for DCO1.
Testing of 1st key secondary endpoint will proceed as follows according to the below two 
scenarios regarding significance on the primary endpoint:
1. If the Primary endpoint is not statistically significant at DCO1, then the key secondary 
variables are not tested at DCO1. If the primary endpoint is statistically significant at DCO2, 
then the 1st key secondary endpoint will be tested at the remaining alpha left assuming it 
would have been tested at 0.02 at DCO1. Thus, if the IF is 95.2% at DCO1, it will be tested at 
0.049647668 (two-sided) at DCO2. If the IF is higher than 95.2%, then the test at DCO2 will 
be conducted at a higher alpha calculated using Haybittle-Peto approach. If the IF is 100%, it 
will be then tested at 0.05 (two-sided). 
2. If the primary endpoint is statistically significant at DCO1, then the 1st Key secondary 
endpoint will be tested at 0.02. If the IF at DCO1 is 100% then it will be tested at 0.05.
The same approach will be applied to the testing of the 2nd key secondary endpoint based on 
the significance of the 1st key secondary endpoint, using their corresponding IF and alpha 

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levels.  
9.2
Sample Size Determination
Approximately 212 participants will be enrolled to achieve approximately 146 participants 
randomly assigned to study intervention. 
Randomisation will be stratified by average baseline PAINS-pNF chronic target PN pain score 
and geographical region. The number of participants randomised will be capped at 
approximately 106 participants with an average baseline PAINS-pNF chronic target PN pain 
score ≥ 3 and approximately 40 participants with an average baseline PAINS-pNF chronic 
target PN pain score < 3.
Enrolled
Estimated 212 participants
Randomly assigned
Selumetinib: Estimated 73 participants
Placebo: Estimated 73 participants
Note: “Enrolled” means a participant’s 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 are not randomly assigned in the study, are 
considered ”screen failures”, unless otherwise specified by the protocol.
With a sample size of 73 participants per arm, a Fisher’s Exact Test with a two-sided alpha of 
5% will have >99% power to detect the difference between selumetinib ORR of 20% and 
placebo ORR of 0%. The ORR of 20% in the selumetinib arm by end of Cycle 16 is assumed 
from ad hoc modelling performed using the SPRINT NCI and ICR data and the Adult NF1 
NCI study response rates. The ORR of 0% in the placebo arm is assumed because at the end 
of Cycle 16, participants randomised to placebo will only have received 4 cycles of 
selumetinib post-crossover, therefore any response detected post-crossover at end of Cycle 12 
will be unconfirmed. Spontaneous shrinkage ≥20% during the first 12 cycles of placebo 
treatment is also not expected (Akshintala et al 2020).
Forty-two participants per arm are required for the study to have 90% power to detect a 
treatment difference of ≥ -2 in the 1st key secondary endpoint change from baseline of PAINS-
pNF chronic target PN pain score (assuming an SD of 2.8) in favour of selumetinib compared 
with placebo at a two-sided alpha level of 5%. To allow for approximately 20% drop out (ie, 
participants without at least one postbaseline average cycle PAINS-pNF chronic target PN 
pain score), 106 participants with a baseline PAINS-pNF chronic target PN pain score of ≥ 3 
will be randomised in a 1:1 selumetinib: placebo allocation. There is no formal sample size 
calculation regarding randomising 40 participants with baseline PAINS-pNF chronic target PN 
pain score of < 3; however, this is deemed sufficient to ensure the target population of adults 

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with NF1 and symptomatic, inoperable PN (including those with little or no baseline PN pain) 
are represented.
By assuming a 20% drop out (i.e, participants without at least one post baseline PlexiQoL 
total score), 58 participants per arm will provide at least 80% power to detect a treatment 
difference at Cycle 12 in the 2nd key secondary endpoint change from baseline of PlexiQoL 
total score (assuming an SD of 2.3) of at least -1.2 in favour of selumetinib compared with 
placebo at a two-sided alpha level of 5%. Refer to Table 11. to some scenarios for the 
statistical power for the 2nd key secondary endpoint with different mean difference in the 
change from baseline of the PlexiQoL total score at Cycle 12 between the two treatment 
groups. This range of possible treatment effects for selumetinib that could be observed in a 
multinational population was extrapolated based on the differences observed in other HRQoL 
scores in other rare disease studies as compared to an Adult selumetinib cohort (Study 
D1346C00011). 
Table 11 Scenarios for the power of the second key secondary endpoint 
Mean Treatment Difference
Statistical Power
-0.7
37%
-0.8
47%
-0.9
56%
-1
65%
-1.1
73%
-1.2
80%
-1.3
86%
-1.4
91%
-1.5
94%
-1.6
96%
-1.7
98%
If it is anticipated that 20% or more of participants (across blinded study intervention groups) 
withdraw prior to the end of Cycle 16, for reasons other than progression, then recruitment 
rates withstanding, enrolment will continue to randomise at least 50% of the total number of 
drop-out participants to ensure the primary endpoint is adequately powered.
9.3
Populations for Analyses
The following populations are defined:

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Table 12
Populations for Analysis
Population/analysis set
Description
Enrolled
All participants who sign the ICF.
FAS
All participants who are randomised to study intervention in the study. Treatment 
groups will be compared on the basis of randomised study intervention, 
regardless of the study intervention actually received. Participants who were 
randomised but did not subsequently receive study intervention are included in 
the analysis in the treatment group to which they were randomised.
Measurable PN FAS
All participants who are randomised to study intervention in the study with 
measurable target PN at baseline per ICR. Treatment groups will be compared on 
the basis of randomised study intervention, regardless of the study intervention 
actually received. Participants who were randomised but did not subsequently 
receive study intervention are included in the analysis in the treatment group to 
which they were randomised.
Pain FAS
All participants with a baseline PAINS-pNF chronic target PN pain intensity 
score ≥ 3. Treatment groups will be compared on the basis of randomised study 
intervention, regardless of the intervention actually received. Participants who 
were randomised but did not subsequently receive study intervention are included 
in the analysis in the treatment group to which they were randomised. 
Selumetinib FAS 
All participants who are randomised to selumetinib with measurable target PN at 
baseline per ICR and who have received at least one dose of selumetinib.
Extended selumetinib 
FAS
All participants who are randomised to study intervention in the study with 
measurable target PN at baseline per ICR and who have received at least one 
dose of selumetinib, ie including participants randomised to placebo who 
crossover to selumetinib treatment. 
Safety analysis set
The Safety analysis set will consist of all enrolled participants who received any 
amount of study intervention. Safety data will be summarised according to the 
treatment received. 
PK analysis set
All participants assigned to study intervention who take at least one dose of study 
intervention for whom any post-dose reportable PK concentration is available and 
who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses.
Fed measurable PN FAS
All participants who are randomised to study intervention in the study with 
measurable target PN at baseline per ICR, who have received at least one dose of 
selumetinib in fed state (i.e participant can eat at any time point in relation to 
each selumetinib intake without continuing to observe the fasting restriction after 
the end of Cycle 24) and who have at least one evaluable scan per ICR 
assessment in fed state at end of Cycle 30 or later. Refer to Section 5.2.1 for the 
definition of participant fed state.
9.4
Statistical Analyses
The SAP will be finalised prior to DCO1 database lock and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 

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summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
9.4.1
General Considerations
The below mentioned general principles will be followed: 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will 
be summarised by the number of observations, mean, SD, median, upper and lower quartiles, 
minimum, and maximum. For log-transformed data it is more appropriate to present geometric 
mean, CV, median, minimum and maximum. Categorical variables will be summarised by 
frequency counts and percentages for each category.
Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding treatment group. Overall totals will be calculated for baseline summaries only.
Detail relating to handling the potential impact of COVID-19 on analyses will be detailed in 
the SAP.
For safety endpoints the last observation before the first dose of study intervention will be 
considered the baseline measurement unless otherwise specified.
The randomised period is defined as follows:

For participants randomised to selumetinib: date of first dose of selumetinib until one day 
prior to date of Cycle 13 study intervention Day 1 or date of study intervention 
discontinuation (whichever occurs first). 

For participants randomised to placebo: date of first dose of placebo until one day prior to 
the date of first selumetinib intake (post crossover) or date of study intervention 
discontinuation (whichever occurs first).
Full details for handling missing data and definition of other study periods will be provided in 
the SAP.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint
9.4.2.1.1
Calculation of PN Assessment
Independent Central Review REiNS assessment
The ICR will first determine the tumour volume (mL) of the target PN at the pre-treatment 
MRI using volumetric analysis. Then follow-up scans of the same target PN will be analysed 
to calculate the target PN tumour volume (mL) and percentage change in target PN volume 
from baseline.

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For each participant, the target PN tumour response (CR, confirmed CR; PR, confirmed PR; 
stable disease or PD) at each post-baseline scan will be programmatically derived from the 
percentage change in target PN volume. If a participant has had a tumour assessment that 
cannot be evaluated, then the participant will be assigned a target PN tumour response of NE. 
This will be repeated for one non-target PN (if relevant). 
Further details of the derivation of target PN tumour response, non-target PN tumour response 
and overall response will be detailed in the SAP.
9.4.2.1.2
Objective Response Rate by end of Cycle 16 
The primary endpoint objective response rate is defined as the proportion of participants 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 PR (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) by end of Cycle 16 as determined by ICR per REiNS criteria.
The primary analysis will include all randomised participants with measurable target PN at 
baseline as determined by ICR (Measurable PN FAS).  Any confirmed CR or a confirmed PR 
at or prior to end of Cycle 16 which occurred after a subsequent NF1-PN treatment (following 
study intervention discontinuation) will not be included in the numerator for the ORR 
calculation.
Supportive evidence of the primary endpoint of ORR by end of Cycle 16 will include: 

Changes in target PN volume (absolute and percentage change from baseline) over time 
in participants randomised to selumetinib and placebo. For participants randomised to 
placebo, these will include data prior and post selumetinib treatment initiation.
Full details of the derivation of ORR while on-treatment and supportive derivations will be 
documented in the SAP
9.4.2.1.3
Analysis Methods
The primary endpoint estimand is based on all randomised participants with measurable target 
PN at baseline per ICR (Measurable PN FAS). 
Data obtained using on-treatment MRI volumetric assessments from first dose up until 
progression (if progression occurs prior to end of Cycle 16) or the last evaluable assessment 
up to and including end of Cycle 16 assessment in the absence of progression will be included 
in the primary endpoint assessment of ORR. 
Participants who discontinue randomised treatment without progression, receive a subsequent 
NF1-PN therapy and then respond at or prior to end of Cycle 16 will not be included as 

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responders in the primary endpoint ORR by end of Cycle 16. Participants with no post-
baseline MRI assessments up to and including end of Cycle 16 will be considered as non-
responder (ie, not having a cCR or cPR).
Intercurrent events are addressed as follows:

Post randomised study intervention discontinuation scans will not be included in the 
analysis assuming a while-on-treatment strategy to the intercurrent event of 
randomised study intervention discontinuation (including early crossover from placebo 
and progression) prior to end of cycle 16 due to any reason. 

Scans after the first 28 days of a prolonged study intervention interruption until study 
intervention has recommenced for at least 28 days will not be included in the analysis, 
assuming a while-on-treatment strategy to the intercurrent event of prolonged study 
intervention interruption (defined as a study intervention interruption greater than or 
equal to 28 days).

Scans after target PN resection will be included in the analysis assuming a treatment 
policy approach to the intercurrent event of target PN resection. 

Scans after subsequent NF1-PN treatment will not be included in the analysis 
assuming a while-on-treatment strategy to the intercurrent event of subsequent NF1-
PN treatment.
The primary endpoint ORR will be compared at the landmark end of Cycle 16 between 
selumetinib versus placebo using a Fisher’s exact test. ORR by end of Cycle 16 in each 
treatment group will be presented with corresponding 2-sided exact 95% CI based on the 
Clopper Pearson method (Clopper and Pearson 1934). The risk difference and 95% CI based 
on the Miettinen-Nurminen (score) method (Miettinen and Nurminen 1985) will also be 
presented.
Change in target PN volume will be analysed using descriptive statistics and trajectory plots.
A supplementary analysis will be performed including all randomised participants (FAS).
Full details of the primary endpoint ORR analyses and supportive analyses will be 
documented in the SAP.
9.4.2.2
Key Secondary Endpoints
9.4.2.2.1
PAINS-pNF chronic target PN pain intensity
The key secondary estimand is the difference of the means in the change from baseline in 
PAINS-pNF chronic target PN pain intensity score at Cycle 12 between selumetinib and 
placebo, amongst participants with a PAINS-pNF chronic target PN pain intensity score ≥ 3 at 

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baseline (Pain FAS) and at least one post-baseline average cycle PAINS-pNF chronic target 
PN pain intensity score. Intercurrent events are addressed as follows:

Changes to participants’ chronic PN pain medication will be included assuming the 
treatment policy strategy to the intercurrent event of changes in participant’s chronic 
PN pain medication.

Post randomised study intervention discontinuation PAINS-pNF scores will not be 
collected and will be modelled through direct likelihood techniques assuming a 
hypothetical strategy to the intercurrent event of randomised study intervention 
discontinuation prior to end of cycle 12 due to any reason. 

PAINS-pNF scores after early crossover from placebo to selumetinib in participants 
with documented progression on imaging (as determined by ICR per REiNS criteria) 
will be set to missing assuming a while-on-treatment strategy to the intercurrent event 
of early crossover from placebo to selumetinib. 

PAINS-pNF scores after the first 28 days of a prolonged study intervention  
interruption until day prior to study intervention recommencement will be set to 
missing assuming a while-on-treatment strategy to the intercurrent event of prolonged 
study intervention interruption.

PAINS-pNF scores after a target PN resection will be included in the analysis 
assuming a treatment policy approach to the intercurrent event of target PN resection. 
A PAINS-pNF chronic target PN pain intensity score ≥ 3 at baseline is used to take into 
account ceiling effects. Participants with a PAINS-pNF chronic target PN pain intensity score 
< 3 at baseline have very little or no possibility of improvement.
The response variable for a cycle will be the average cycle PAINS-pNF chronic target PN pain 
score change from baseline defined as the average of the available daily PAINS-pNF chronic 
target PN pain scores for the 28 days up to and including the last day of the cycle minus the 
baseline PAINS-pNF chronic target PN pain score. The average cycle PAINS-pNF chronic 
target PN pain score will only be derived if the participant meets the criteria of having at least 
4 daily pain scores out of 7 days for at least 3 non-overlapping 7-day periods in the 28-day 
cycle. Baseline PAINS-pNF chronic target PN pain score is defined as the average of the 
available daily PAINS-pNF chronic target PN pain scores in the screening period. During this 
time, participants must complete their pain diary for at least 4 days out of 7 days for at least 
2 non-overlapping 7-day periods in order to determine the participant’s average baseline 
chronic target PN pain intensity score.

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Scoring
Each of the two items on the PAINS-pNF (usual [chronic] pain and spikes of PN pain) are 
treated as an individual score ranging from 0 to 10. For example, when administered daily for 
7 days consecutively, this results in 7 usual (chronic) PN pain scores and 7 spikes of PN pain 
scores.
Analysis Methods
For each participant, mean change from baseline in PAINS-pNF chronic target PN pain 
intensity score at each cycle will be calculated using the average cycle PAINS-pNF chronic 
target PN pain score minus baseline PAINS-pNF chronic target PN pain score. 
The difference in the mean change from baseline at Cycle 12 will be analysed for PAINS-pNF 
chronic target PN pain intensity using a mixed model repeated measures (MMRM) analysis. 
The MMRM model will include treatment, cycle number and geographical region as 
categorical fixed effects, the baseline PAINS-pNF chronic target PN pain intensity score as a 
continuous covariate and treatment-by-cycle number and baseline PAINS-pNF score-by-cycle 
number interactions. Parameters will be estimated with the restricted maximum likelihood 
(REML) approach and the Kenward-Roger approximation is used to estimate the degrees of 
freedom.  An unstructured covariance matrix will be used to allow for unequal treatment 
variance and to model the correlation between different treatment measurements within the 
same subject. If the fit of the unstructured covariance structure fails to converge, the following 
covariance structures will be used in order until convergence is reached: toeplitz with 
heterogeneity, autoregressive with heterogeneity, toeplitz, autoregressive and compound 
symmetry. 
The approach to examine missingness will be described in the SAP.  
In addition, supplementary analyses for alternative estimands will be detailed in the SAP, 
including specifying a composite strategy for the intercurrent events of study intervention 
discontinuation and increase in chronic PN pain medication (based on data collected in the 
e-Diary and investigator’s assessment of pain medication as outlined  in Section 8.1.8.3) such 
that data not collected post study intervention discontinuation and potential confounding from 
pain medication are addressed.
9.4.2.2.2
PlexiQoL
The key secondary estimand is the difference of the means in the change from baseline in 
PlexiQOL total score at Cycle 12 between selumetinib and placebo, amongst FAS participants 
with an baseline PlexiQOL total score and at least one post-baseline PlexiQOL total score. 
Intercurrent events are addressed as follows:

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
Post randomised study intervention discontinuation PlexiQOL scores will not be 
collected and will be modelled through direct likelihood techniques assuming a 
hypothetical strategy to the intercurrent event of randomised study intervention 
discontinuation prior to end of cycle 12 due to any reason. 

PlexiQOL scores after early crossover from placebo to selumetinib in participants 
with documented progression on imaging (as determined by ICR per REiNS criteria) 
will be set to missing assuming a while-on-treatment strategy to the intercurrent event 
of early crossover from placebo to selumetinib. 

PlexiQOL scores after the first 28 days of a prolonged study intervention interruption 
until day prior to study intervention recommencement will be set to missing assuming 
a while-on-treatment strategy to the intercurrent event of prolonged study intervention 
interruption.

PlexiQOL scores after a target PN resection will be included in the analysis assuming 
a treatment policy approach to the intercurrent event of target PN resection. 
The response variable for a specific cycle will be the PlexiQOL change from baseline defined 
as the PlexiQOL total score at that cycle minus the baseline PlexiQOL total score. 
Scoring
Each statement on the PlexiQoL is given a score of 1 = True or 0 = Not true. A score of “1” is 
given where the item is affirmed, indicating adverse quality of life. According to the PlexiQoL 
user manual, it is recommended that for respondents with between one and three missing 
responses (that is, cases with no more than 20% missing data), the total score is calculated as 
follows: all item scores are summed to give a total score that ranges from 0 (good QoL) to 18 
(poor QoL). This total score is then divided by the number of non-missing items and 
multiplied by 18. Cases with more than three missing responses cannot be allocated a total 
score.
Difference in change from baseline in PlexiQoL items between selumetinib and placebo will 
be evaluated at post-baseline cycles and overall over the randomised treatment period. 
The change from baseline in PlexiQoL total score over the duration of the study will also be 
evaluated.
Analysis Methods
For each participant, change from baseline in PlexiQOL total score at the end of each cycle 
where PlexiQOL is measured during the randomised period (cycles 2, 4, 8 and 12) will be 
calculated.  

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The difference in the mean change from baseline at Cycle 12 will be analysed for PlexiQOL 
total score using a MMRM analysis. The MMRM model will include treatment, cycle number 
and geographical region as categorical fixed effects, the baseline PlexiQOL total score as a 
continuous covariate and treatment-by-cycle number and baseline PlexiQOL total score-by-
cycle number interactions. Parameters will be estimated with the restricted maximum 
likelihood (REML) approach and the Kenward-Roger approximation is used to estimate the 
degrees of freedom.  An unstructured covariance matrix will be used to allow for unequal 
treatment variance and to model the correlation between different treatment measurements 
within the same subject. If the fit of the unstructured covariance structure fails to converge, 
the following covariance structures will be used in order until convergence is reached: toeplitz 
with heterogeneity, autoregressive with heterogeneity, toeplitz, autoregressive and compound 
symmetry. 
The approach to examine missingness will be described in the SAP.  
In addition, supplementary analyses for alternative estimands will be detailed in the SAP, 
Full details of the analysis of PlexiQoL items will be documented in the SAP.
9.4.2.3
Secondary Endpoints
9.4.2.3.1
Objective Response Rate (single-arm)
Objective response rate is defined as described in Section 9.4.2.1.2. 
This ORR analysis will include all participants randomised to selumetinib with measurable 
target PN at baseline per ICR and who received at least one dose of selumetinib (Selumetinib 
FAS), ie, single arm assessment of ORR. Data obtained while on-treatment from first 
selumetinib dose up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR. Any confirmed CR or a confirmed PR 
which occurred after a subsequent NF1-PN treatment (following study intervention 
discontinuation) will not be included in the numerator for the ORR calculation (where the 
selumetinib FAS will be the denominator).
Supportive evidence of the ORR (single-arm) will include: 

A supplementary analysis including all participants with measurable target PN at baseline 
per ICR who received at least one dose of selumetinib (Extended selumetinib FAS). In 
this analysis, the baseline MRI scan for participants randomised to placebo will be 
defined as the last MRI scan performed on placebo treatment prior to crossing over to 
selumetinib treatment.

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
The BOR, defined as the best objective response recorded from the start of study 
intervention until progression or the last evaluable MRI assessment in the absence of 
progression, will also be summarised by category (confirmed CR, CR, confirmed PR, PR, 
stable disease, PD, or NE) and treatment arm.
Analysis Methods
ORR will be presented with corresponding two-sided exact 95% CI based on the Clopper 
Pearson methods (Clopper and Pearson 1934). 
The BOR will be summarised with descriptive statistics for both the selumetinib FAS and the 
extended selumetinib FAS.
Full details of the analyses and supportive analyses will be documented in the SAP.
9.4.2.3.2
Duration of Response
Duration of Response is derived using while on-treatment MRI volumetric assessments. The 
DoR will be defined as the time from the date of first documented response (which is 
subsequently confirmed) until date of documented progression as assessed by ICR per REiNS 
criteria or death due to any cause (ie, date of PFS event or censoring – date of first 
documented response + 1). 
The analysis will include all participants randomised to selumetinib with measurable target 
PN at baseline per ICR who received at least one dose of selumetinib (Selumetinib FAS) and 
with a confirmed CR or confirmed PR prior to study intervention discontinuation. Full details 
of the derivation of DoR while on-treatment, and censoring rules will be documented in the 
SAP. 
A supplementary analysis will be performed including all participants who received at least 
one dose of selumetinib and with a confirmed CR or confirmed PR prior to study intervention 
discontinuation. In this analysis, the baseline MRI scan for participants randomised to placebo 
will be defined as the last MRI scan performed on placebo treatment prior to crossing over to 
selumetinib treatment.
Analysis Methods
Descriptive data will be provided for the DoR in responding participants, including the 
associated Kaplan-Meier curves. Full details of the DoR summaries will be documented in the 
SAP.
9.4.2.3.3
Progression Free Survival 
Progression free survival will be derived using while on-treatment MRI volumetric 
assessments and is defined as the time from the date of first selumetinib dose until date of 

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progression by ICR per REiNS criteria or death (due to any cause), ie, date of event or 
censoring – date of the first dose of selumetinib + 1. 
Participants who have not progressed or died at the time of analysis will be censored at the 
time of the latest date of assessment from their last evaluable REiNS assessment. 
The analysis will include all participants randomised to selumetinib with measurable target PN 
at baseline per ICR who received at least one dose of selumetinib (Selumetinib FAS).
A supplementary analysis will be performed including all participants with measurable target 
PN at baseline per ICR who received at least one dose of selumetinib (Extended Selumetinib 
FAS). In this analysis, the baseline MRI scan for participants randomised to placebo will be 
defined as the last MRI scan performed on placebo treatment prior to crossing over to 
selumetinib treatment.
Full detail for the derivation of PFS while on-treatment and censoring rules will be 
documented in the SAP.
Analysis Methods
Descriptive data will be provided for PFS, including the associated Kaplan-Meier curve. Full 
details of PFS summaries will be documented in the SAP.
9.4.2.3.4
Time to Progression
Time to progression will be derived using while on-treatment MRI volumetric assessments. 
Time to progression will be defined as the time from the date of first selumetinib dose until 
date of documented objective disease progression by ICR per REiNS criteria, ie, date of 
objective disease progression or censoring – date of first dose of selumetinib + 1.
The analysis will include all participants randomised to selumetinib with measurable target PN 
at baseline per ICR who received at least one dose of selumetinib (Selumetinib FAS).
A supplementary analysis will be performed including all participants with measurable target 
PN at baseline per ICR who received at least one dose of selumetinib (Extended selumetinib 
FAS). In this analysis, the baseline MRI scan for participants randomised to placebo will be 
defined as the last MRI scan performed on placebo treatment prior to crossing over to 
selumetinib treatment. 
Full detail for the derivation of TTP, while on-treatment and censoring rules will be 
documented in the SAP.
Analysis Methods
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Full details of TTP summaries will be documented in the SAP.
9.4.2.3.5
Time to Response
Time to response will be derived using while on-treatment MRI volumetric assessments and is 
defined as the time from date of first dose of selumetinib until the date of first documented 
objective response (which is subsequently confirmed), by ICR per REiNS criteria, ie, date of 
first documented objective response – date of first dose of selumetinib + 1. 
Data obtained from the first selumetinib dose up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of TTR. 
The analysis will include all participants randomised to selumetinib with measurable target PN 
at baseline per ICR and who received at least one dose of selumetinib (Selumetinib FAS) and 
with a confirmed CR or confirmed PR prior to selumetinib discontinuation. 
A supplementary analysis will be performed including all participants with measurable target 
PN at baseline per ICR who received at least one dose of selumetinib (Extended selumetinib 
FAS) and with a confirmed CR or confirmed PR prior to selumetinib discontinuation. In this 
analysis, the baseline MRI scan for participants randomised to placebo will be defined as the 
last MRI scan performed on placebo treatment prior to crossing over to selumetinib treatment.
Full details of the derivation of TTR, while on-treatment and censoring rules will be 
documented in the SAP.
Analysis Methods
Descriptive data will be provided for TTR. Full details of TTR summaries will be documented 
in the SAP.
9.4.2.3.6
Best Percentage Change from Baseline in Target PN
The difference in the best percentage change from baseline in target PN volume by ICR per 
REiNS criteria between selumetinib and placebo during the randomised period will be 
assessed. 
The best percentage change from baseline in target PN volume will be derived using while on-
treatment MRI volumetric assessments during the randomised period (see definition in Section 
9.4.1). The analysis will include a subset of all participants randomised to study intervention 
with measurable target PN at baseline per ICR (Measurable PN FAS) with at least one post-
baseline target PN volume during the randomised period. 
Analysis Methods
Full details of the best percentage change from baseline in target PN volume analysis will be 
documented in the SAP.

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9.4.2.3.7
Chronic Target PN Pain Palliation
Chronic target PN pain palliation is defined as an improvement of ≥ 2 in average cycle 
PAINS-pNF chronic target PN pain intensity score and no increase in chronic PN pain 
medication compared to baseline for that cycle. The average cycle PAINS-pNF chronic target 
PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN 
pain scores for the 28 days up to and including the last day of the cycle. The average cycle 
PAINS-pNF chronic target PN pain score will only be derived if the participant meets the 
criteria of having at least 4 daily pain scores out of 7 days for at least 3 non-overlapping 7-day 
periods in the 28-day cycle.
A chronic target PN pain palliation responder will be identified at each cycle as participants 
with an average cycle PAINS-pNF chronic target PN pain score decrease from baseline 
≥2 points who also had no increase in chronic PN pain medication use during the specific 
cycle based on the e-Diary (as outlined in Section 8.1.8.3). A sensitivity analysis will be 
performed, where no increase in pain medication use is defined based on investigator 
assessment.
Pain palliation will be assessed in post baseline cycles during the randomised period (see 
definition in Section 9.4.1) in participants in the Pain FAS.
Analysis Methods
The difference in the proportion of participants with chronic target PN pain palliation will be 
analysed at post-baseline cycles and overall over the randomised treatment period between the 
selumetinib and placebo arms.
Full detail of the analysis of chronic target PN pain palliation including sensitivity analyses 
will be documented in the SAP.
9.4.2.3.8
Time to Chronic Target PN Pain Palliation
Time to chronic target PN pain palliation is defined as the time from the first dose of study 
drug until the cycle of chronic target PN pain palliation.
Time to chronic target PN pain palliation will be evaluated between selumetinib and placebo 
during the randomised period (see definition in Section 9.4.1) in participants in the Pain FAS. 
Full detail for the derivation of time to chronic target PN pain palliation and censoring rules 
will be documented in the SAP.
Analysis Methods
Full details of time to chronic target PN pain palliation analysis will be documented in the 
SAP.

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9.4.2.3.9
Pain Medication
Pain medication use in each treatment group (selumetinib and placebo) at  as reported using 
the e-Diary and as assessed by the investigator will be analysed (as described in Section 
8.1.8.3) at post-baseline cycles and overall over the randomised treatment period.
Pain medication use will be assessed in evaluable participants in the FAS. 
Analysis Methods
Full details of the analysis of pain medication use will be documented in the SAP.
9.4.2.3.10
Pain Interference
Scoring 
Responses to individual PII-pNF items are summed and divided by the number of items 
answered to yield a pain interference total score ranging from 0 to 6 for each assessment.
Difference in change from baseline in PII-pNF pain interference total score between 
selumetinib and placebo will be assessed at post-baseline cycles and overall over the 
randomised treatment period. The response variable is the absolute change in end of cycle PII-
pNF pain interference total score from baseline.
Analysis Methods
The analysis population will be a subset of the FAS, including all randomised participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment. 
For the analysis of PII-pNF pain interference total score over the duration of the study in 
participants randomised to placebo, data prior and post selumetinib treatment initiation will be 
provided.
A subgroup analysis will be performed by baseline PAINS-pNF chronic target PN score 
group. Full details of the analysis of PII-pNF pain interference total score will be documented 
in the SAP.
9.4.2.3.11
Physical Functioning
Scoring
Three items selected from the PROMIS physical function item bank will be used in this study. 
The items capture physical function impacts separate from those related to pain interference. 
Raw scores are converted to a T-score. 
Difference in change from baseline in PROMIS Physical Function scores between selumetinib 
and placebo will be assessed at post-baseline cycles and overall over the randomised treatment 

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period. 
The change from baseline in PROMIS items over the duration of the study will also be 
evaluated.
Analysis Methods
The analysis population will be a subset of the FAS, including all randomised participants 
with an evaluable baseline assessment and at least one evaluable post-baseline assessment. 
For the analysis of PROMIS items over the duration of the study in participants randomised to 
placebo, data prior and post selumetinib treatment initiation will be provided.
A subgroup analysis will be performed by baseline PAINS-pNF chronic target PN score 
group. Full details of the analysis of PROMIS items will be documented in the SAP.
9.4.2.3.12
PedsQL (NF1 module Acute Version 3.0-Adult Report) Skin Sensations Domain 
Scoring 
Items are rated on a 5-point Likert scale from 0 (Never) to 4 (Almost always), and are 
reversed scored and linearly transformed to a 0-100 scale as follows: 0 = 100, 1 = 75, 2 = 50, 
3 = 25, 4 = 0. Domain scores are calculated by the sum of all the items over the number of 
items answered.
Difference in change from baseline in the Skin Sensations domain of the PedsQL 
(NF1 module acute Version 3.0 – adult report) between selumetinib and placebo will be 
assessed at post-baseline cycles and overall over the randomised treatment period. 
The change from baseline in the Skin Sensations domain of the PedsQL NF1 module acute 
Version 3.0 – adult report over the duration of the study will also be evaluated.
Analysis Methods
The analysis population will be a subset of the FAS with an evaluable baseline assessment and 
at least one evaluable post-baseline assessment. 
For the analysis of PedsQL NF1 module – adult form Skin Sensations items over the duration 
of the study, in participants randomised to placebo, data prior and post selumetinib treatment 
initiation will be provided.
A subgroup analysis will be performed by baseline PAINS-pNF chronic target PN score 
group. Full details of the analysis of PedsQL NF1 module – adult form items will be 
documented in the SAP.

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9.4.2.3.13
EQ-5D-5L
Scoring
The EQ-5D-5L questionnaire comprises 6 questions that cover 5 dimensions of health 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a VAS. For 
each dimension, respondents select which statement best describes their health on that day 
from a possible 5 options of increasing levels of severity (no problems, slight problems, 
moderate problems, severe problems, and unable to/extreme problems). 
A unique EQ-5D health state, termed the EQ-5D-5L profile, is reported as a 5-digit code with 
a possible 3125 health states based on these responses. For example, state 11111 indicates no 
problems on any of the 5 dimensions. This EQ-5D-5L profile will be converted into a 
weighted health state utility value, termed the EQ-5D index, by applying a country-specific 
equation to the profile that represents the comparative value of health states. This equation is 
based on national 5-level valuation sets elicited from the general population, and the base case 
will be the UK perspective.
Respondents also assess their health today using the EQ-VAS, which ranges from 0 (worst 
imaginable health) to 100 (best imaginable health).
The following endpoints will be evaluated at post-baseline cycles and overall over the 
randomised treatment period:

Difference in change from baseline in EQ-5D-5L score between selumetinib and 
placebo.

Difference in change from baseline in EQ-VAS between selumetinib and placebo. 
The change from baseline in EQ-5D-5L score and EQ-VAS over the duration of the study will 
also be evaluated.
Analysis Methods
The analysis population will be a subset of the FAS, with an evaluable baseline assessment 
and at least one evaluable post-baseline assessment. For the analysis of EQ-5D-5L and 
EQ-VAS over the duration of the study in participants randomised to placebo, data prior and 
post selumetinib treatment initiation will be provided.
A subgroup analysis will be performed by baseline PAINS-pNF chronic target PN score 
group. Full details of the analysis of EQ-5D-5L and EQ-VAS will be documented in the SAP.

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9.4.2.3.14
ECOG Performance Status
ECOG performance status will be summarised by visit and treatment group.
9.4.2.4
Exploratory Endpoints
Full details of the analysis of exploratory endpoints will be provided in the SAP.
9.4.3
Safety
Safety analyses will be performed based on the Safety Analysis Set. Safety data will be 
presented using descriptive statistics unless otherwise specified.
Baseline: In general, the baseline value for statistical analysis is the last non-missing value 
prior to administration of the first dose of IP. Details are described in the SAP.
9.4.3.1
Adverse Events
Adverse events will be coded using the most recent version of MedDRA that will have been 
released for execution at AstraZeneca/designee.
Adverse events will be presented for each treatment group by SOC and/or PT covering 
number and percentage of participants reporting at least one event and number of events 
where appropriate.
An overview of AEs will present for each treatment group the number and percentage of 
participants with any AE, AESIs, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of study treatment, as well as AEs leading to study treatment dose 
interruptions and AEs leading to study treatment dose reductions.
Separate AE tables will be provided that take different factors into consideration, including 
relationship as assessed by the investigator, maximum CTCAE grade, seriousness, death and 
events leading to discontinuation of study intervention as well as other action taken related to 
study treatment, events of special interest and other significant AEs.
An additional table will present number and percentage of participants with most common 
AEs. Most common (eg, frequency of > x%, ≥ x%) will be defined in the SAP.
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of participants in any treatment group.
Key participant information will be presented for participants with AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of study intervention.
An AE listing for the safety analysis set will cover details for each individual AE.
Full details of AE analyses will be provided in the SAP.

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9.4.3.2
Treatment emergent AEs 
The following events are considered treatment emergent:
Adverse events with an onset date on or after first dose of IP and within 30 days after last dose 
of IP or up to the day prior to start of subsequent therapy, whichever comes first. 
Worsening of pre-existing events on or after first dose of IP and within 30 days after last dose 
of IP or up to the day prior to start of subsequent therapy, whichever comes first. 
Exposure-adjusted treatment emergent AEs will also be presented.
9.4.3.3
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, min, Q1, median, Q3, and max. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline. 
Details of vital sign analyses will be provided in the SAP.
9.4.3.4
Laboratory Parameters
Laboratory parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, min, Q1, median, Q3, and max. 
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline. 
Details of laboratory analyses will be provided in the SAP. 
9.4.3.5
Other Safety Endpoint(s)
Other safety data, including ophthalmologic assessments, will be summarised using 
descriptive statistics.
9.4.4
Other Analyses
9.4.4.1
Pharmacokinetics
Pharmacokinetic parameters will be derived for selumetinib and N-desmethyl selumetinib 
using plasma concentrations, including, but not limited to: 

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Selumetinib:

Cmax, AUC(0-6), AUC(0-8), AUClast, CL/F, Vss/F, tmax, tlast derived after multiple 
dose administration.
N desmethyl selumetinib:

Cmax, AUC(0-6), AUC(0-8), AUClast, tmax, tlast derived after multiple dose 
administration.

MPAUC and MPCmax after multiple dose administration. MPAUC will be based on 
either AUC(0-6) or AUC(0-8) depending on which has the most reportable values.
The plasma selumetinib and N-desmethyl selumetinib concentrations and the PK parameters 
will be listed and presented in tabular and graphical form by analyte based on the PK Analysis 
Set.
Geometric mean (± geometric SD) plasma concentration versus nominal sampling time will 
be plotted in a linear and semi-logarithmic scale with all treatments (periods) overlaid on the 
same figure and with a separate plot for each analyte.
Further data presentation and reporting details will be provided in the SAP.
Details of population PK exposure response/safety analyses will be described in the modelling 
analysis plan finalised before database lock. The population PK exposure response/safety 
analyses will be presented separately from the main clinical study report. 
9.4.4.2
Biomarker Analysis

Exploratory biomarkers in plasma will be summarised by scheduled sample time points 
and change from pre-dose and consent to sample re-used.

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.
9.4.4.3
Optional Exploratory Genetic Sample
Data will be reported outside the clinical study report (please see Appendix D).
9.5
Interim Analyses
The SAP will describe the planned interim analyses in greater detail. Significance levels will 

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be adjusted for each endpoint in order to preserve the overall type 1 error (familywise error 
rate) at 5% (two-sided) in the strong sense. Endpoints included in the MTP will be tested 
hierarchically, therefore if the interim analysis indicates significant ORR, then the key 
secondary endpoints will be tested in the following order: 1) PAINS-pNF chronic target PN 
pain intensity score and if this endpoint has a significant p-value then 2) PlexiQOL total score.
The results of these analyses may form the basis of submissions for regulatory approval.
The interim analysis (DCO1) is expected to occur when the 100th randomised participant has 
had the opportunity to complete their end of Cycle 16 assessment. This corresponds to 
approximately 68.5% of the primary endpoint information expected at the primary analysis 
(DCO2). 
The overall alpha of 0.05 (two-sided) will be first assigned to the primary endpoint (ORR by 
end of Cycle 16), of which an alpha of 0.003 (two-sided) will be allocated at the interim 
analysis. If the primary endpoint is statistically significant at the interim analysis, then the 
overall alpha of 0.05 (two-sided) will be re-assigned to the 1st key secondary endpoint (mean 
change from baseline in PAINS-pNF chronic target PN pain intensity score at Cycle 12), and 
an alpha of 0.02 (two-sided) will be allocated to the 1st key secondary endpoint at the interim 
analysis. If the 1st key secondary endpoint is statistically significant at the interim analysis 
then the overall alpha of 0.05 (two-sided) will be re-assigned to 2nd key secondary endpoint 
(change from baseline in PlexiQOL total score at Cycle 12), and an alpha of 0.02 (two-sided) 
will be allocated to the 2nd key secondary endpoint at the interim analysis.
The key secondary endpoints information fractions will be determined at the point of the 
interim analysis:

For the 1st key secondary endpoint: The number of participants with baseline PAINS-pNF 
chronic target PN pain intensity score ≥3 who have the opportunity to complete 12 cycles 
of treatment and have at least one post-baseline average cycle PAINS-pNF chronic target 
PN pain intensity score. 

For the 2nd key secondary endpoint: The number of participants with baseline PlexiQOL 
total score who have the opportunity to complete 12 cycles of treatment and have at least 
one post-baseline PlexiQOL total score. 
Given that when the 100th randomised participant has completed Cycle 16, there will be more 
than 100 participants who will have completed Cycle 12, the information fraction for the key 
secondary endpoints is estimated to be very high at the interim analysis. 
The interim analyses will be performed by a team of unblinded statisticians and programmers 
independent from AstraZeneca. The independent team will inform an unblinded review 

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committee (internal to AstraZeneca but independent from the study team) whether the study 
success criteria specified in Section 9.1 have been met, and if so, the unblinded review 
committee will review the unblinded interim analysis outputs to make the decision whether to 
unblind the study team or not prior to the primary analysis. 
If the interim analysis DCO (DCO1) is due to take place within approximately 4 months or of 
the primary analysis DCO (DCO2), then the interim analysis may not be performed and only 
the primary analysis will be performed. 
For further details on how the overall type 1 error (familywise error rate) is preserved at 5% in 
the strong sense refer to Section 9.1.
9.6
Data Monitoring Committee
Given that the randomised portion of the study is of limited duration, the participant 
population is not considered vulnerable, and the safety profile of selumetinib is well 
established, an IDMC is not deemed to be necessary.
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 protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th World Medical Association General 
Assembly, Fortaleza, Brazil, October 2013 and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, 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 amendments to the 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 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.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to AstraZeneca of a 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 suspected unexpected serious adverse reactions according to local regulatory 
requirements and AstraZeneca policy and forwarded to investigators as necessary.

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
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 a SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the [IB or state other documents] 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 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 study.

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.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.

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 (e-mail address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for one year after completion of the study.

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A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants will be required to sign a statement of informed consent that 
meets the requirements of 21 Code of Federal Regulations 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study centre.

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.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant.
A participant who is rescreened is not required to sign another ICF 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 AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by 
AstraZeneca, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

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The participant’s samples will not be used for any purpose other than those described in the 
study protocol.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
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 http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main D134BC00001 study results 
when they are available. The clinical study and/or summary of main D134BC00001 study 
results may also be available on other websites according to the regulations of the countries in 
which the main D134BC00001 study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on the CRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
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 authority 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.

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
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.

AstraZeneca 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 being conducted in accordance with the currently approved protocol 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 GRAD Schedule. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.
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 reported on the eCRF or 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. All information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical study necessary 
for the reconstruction and evaluation of the study are defined as source documents. 
Source data are contained in source documents (original records or certified copies).
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 act of recruitment is the first site open and will be the study start date.
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. 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.

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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 AstraZeneca or investigator may include but 
are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, AstraZeneca’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) 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.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
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 AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.

AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multicentre studies only in their entirety and not as individual site 
data. In this case, a co-ordinating 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 (other than progression of the 
disease under evaluation) in a participant or clinical study participant administered a study 
intervention and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory 
finding), symptom (for example nausea, chest pain), or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the study intervention. 
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
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, 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.
Adverse events of malignant tumours reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion 
should be used. In certain situations, however, medical judgment on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.

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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 a 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 judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may 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 
judgment 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 National Cancer Institute 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.

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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?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a 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.

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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:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, 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 errors)

Wrong drug administered to participant (excluding IRT errors)

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Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT – 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 
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).

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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
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent specifically to the subsequent 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. The participant will be presented with the option to opt out of the subsequent use of 
the donated samples during the withdrawal process. If the participant decides to opt out, then 
the donated samples will be disposed of. If the participant withdraws consent without opting 
out for the subsequent use of the donated samples, then the samples will be used as per 
protocol.
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 participant’s 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.

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
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
IATA (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, for example, 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, for example, 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 UN3373 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
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant’s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

AstraZeneca will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on selumetinib continues but no longer than 
15 years from the end of the study (as defined in the protocol) or other period as per local 
requirements.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria

For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Previous allogeneic bone marrow transplant.

Transfusion of non-leukocyte depleted blood or blood component within 120 days of 
genetic sample collection.

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
Healthy volunteers and paediatric participant samples will not be collected for the 
Genomics Initiative.
Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main CSP.
Collection of Samples for Genetic Research

The blood sample for this genetic research will be obtained from the participants pre-dose 
at the first dosing visit. Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding participants who may withdraw due to an AE. If 
for any reason the sample is not drawn at the first dosing visit, it may be taken at any visit 
until the last study visit. Only one sample should be collected per participant for genetics 
during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples may be stored for a maximum 
of 15 years from the end of the study (as defined in the protocol), after which they will be 
destroyed. DNA is a finite resource that is used up during analyses. Samples will be 
stored and used until no further analyses are possible or the maximum storage time has 
been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.

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Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A.
Informed Consent

The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The principal investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

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
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.
Statistical Methods

The number of participants that will agree to participate in the genetic research is 
unknown. It is therefore not possible to establish whether sufficient data will be collected 
to allow a formal statistical evaluation or whether only descriptive statistics will be 
generated. A Statistical Analysis Plan may be prepared where appropriate.

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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 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. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the study intervention. 
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.
E 2
Definitions
PHL
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point 
during the study following the start of study intervention irrespective of an increase in alkaline 
phosphatase.
HL
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other 
reason, other than the study intervention, can be found to explain the combination of 
increases, eg, elevated alkaline phosphatase indicating cholestasis, viral hepatitis, another 
drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN.

AST ≥ 3 × ULN.

TBL ≥ 2 × ULN.
Local laboratories being used
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 E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.
E 4
Follow-up
E 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.
E 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 criterion “Important medical event” and causality assessment 
“yes/related” according to CSP process for SAE reporting.

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
For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition. 

The AstraZeneca 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:

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 AstraZeneca Medical Monitor.

Complete the 3 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 AstraZeneca Medical Monitor if there is any uncertainty.
E 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 AstraZeneca 
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 study intervention, 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.

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
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 study intervention:

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.

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 study intervention and 
seriousness criterion 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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E 6
Laboratory Tests
Hy’s Law Lab Tests That May be Performed 
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HbsAg
HCV DNA a
IgM and IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate-deficient transferrin b
Autoimmune hepatitis
Antinuclear antibody
Anti-liver/kidney microsomal antibody
Anti-smooth muscle antibody
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
CMV=cytomegalovirus; DNA=deoxyribonucleic acid; EBV=Epstein-Barr virus; GGT=gamma glutamyl transferase; 
HAV=hepatitis A virus; HBc=hepatitis B core antigen; HbsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
HCV=hepatitis C virus; HEV=hepatitis E virus; HSV=herpes simplex virus; IgG=immune-globulin G; 
IgM=immuno-globulin M; INR=international normalised ratio; LDH=lactate dehydrogenase; RNA=ribonucleic acid.
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive.
b
Carbohydrate-deficient transferrin and transferrin are not available in China. Study teams should amend this list 
accordingly.

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Appendix F
Contraception Requirements
Contraception requirements for this study are as follows.
F 1
Female Participants
Women not of childbearing potential are defined as those who are surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.

Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses > 1 year ago, or had 
chemotherapy-induced menopause with last menses > 1 year ago.
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a nonsterilised male partner must use at least 1 highly 
effective method of contraception (Table F11). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study and continue to 
use it throughout the total duration of the drug treatment and the drug washout period (7 days 
after the last dose of study intervention). 
Non-sterilised male partners of a woman of childbearing potential must use a male condom 
plus spermicide (condom alone in countries where spermicides are not approved) throughout 
this period and until at least one week after the female participant’s last dose of study 
intervention. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Total sexual abstinence is an acceptable method 
provided it is the usual lifestyle of the participant. Female participants should refrain from 
breastfeeding throughout this period.

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F 2
Male Participants with a Female Partner of Childbearing 
Potential
Non-sterilised male participants (including males sterilised by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (one week after the last dose of study intervention) to prevent pregnancy in a partner. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male participants should refrain from sperm donation or banking 
throughout this period.
Vasectomised (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table F11).
F 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table F11. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).

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Table F11
Highly Effective Methods of Contraception (< 1% Failure Rate)
Non-hormonal methods
Hormonal methods
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia)
•
Bilateral tubal occlusion
•
Intrauterine device (provided coils are 
copperbanded)
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) a
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Combined pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Mini pill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.

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Appendix G
Patient-reported Outcomes
G 1
PAINS-pNF
CCI

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CCI
CCI
CCI

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G 2
PII-pNF
CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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G 5
PedsQL NF1 Module Acute Version 3.0-Adult Report (Skin 
Sensations Domain)
G 6
PGIC
CCI

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G 7
PGIS

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Appendix H
Guidance for Management of Specific Adverse Events
H 1
Management of Left Ventricular Ejection Fraction (LVEF) 
Reduction (asymptomatic) or Left Ventricular Systolic 
Dysfunction (LVSD)
ECHO, echocardiogram; LLN, lower limit of normal, LVEF, left ventricular ejection fraction; LVSD, left 
ventricular systolic dysfunction.

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H 2
Management of Creatine Kinase (CK) Elevation
CK, creatine kinase; CTC Common Terminology Criteria; ULN, Upper Limit of Normal. 

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

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H 4
Management of Diarrhoea
CTC, Common Terminology Criteria

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H 5
Management of New or Worsening Dyspnoea
BNP, brain natriuretic peptide; CT, computed tomography; ECG, electrocardiogram; Hb, haemoglobin; ILD, 
interstitial lung disease; P-A, posterior-anterior; WBC, white blood cell 

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H 6
Management of Participants with Rash
H 6.1
Management of Rash
H 6.2
Rash: Adult Treatment Recommendations 

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H 7
Oral Care Management for Events of Oral Mucositis and Dry 
Mouth

Participants should be encouraged to follow a daily oral health care regimes, both before 
and during treatment with selumetinib. 

Participants with a healthy mouth may use non-alcoholic mouthwash 4 to 6 times daily 
(eg, 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 tooth brushing (eg, after 
tea).

Use of a mouthwash immediately after selumetinib intake is recommended. 

The tongue can be gently brushed (if not sore) with a soft toothbrush. 

Participants 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 participant 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). Participants 
with stomatitis should change their toothbrush every 4 to 6 weeks.

Consider culture to rule out herpes simplex.

Consider treating stomatitis at an early stage (CTCAE Grade 1) or as soon as the 
participant complains of a sore mouth. Consider using an oral topical analgesic, with or 
without topical steroids, depending on the participant’s clinical condition and the local 
standard medical practice.

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H 8
Management of Paronychia
CTC, Common Terminology Criteria
Table H12
Treatment Recommendations for AE Paronychia a
Severity
Treatment Recommendations
CTCAE Grade 1
Treat the affected area by soaking in vinegar solution twice daily (1 part vinegar to 
2 parts water) and 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) and systemic antibiotic (Keflex, Clindamycin) and 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 and drainage or surgical management.  
a
If granulation tissue present, consider use of silver nitrate under supervision.
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events

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For participants 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 (eg, pyogenic-granuloma-like lesions). If the periungual 
skin is swollen but intact (whether infectious or non-infectious), silver nitrate is not 
recommended. 
Participants should be cautioned to avoid trauma to the area. Podiatry consult may be 
considered for partial nail removal.
Participants who undergo incision and drainage and are found to have no infectious organisms 
on culture, should be treated as above. If infection is identified, participants may be treated 
with systemic antibiotics (oral tetracyclines).
If paronychia recurs or develops in other fingers or toes, flurandrenolide (eg, 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 I
Cardiovascular Grading
Table I13
Canadian Cardiovascular Society Grading of Angina Pectoris
Grade
Description
I
Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina with 
strenuous or rapid or prolonged exertion at work or recreation.
II
Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or 
stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the few 
hours after awakening. Walking more than two blocks on the level and climbing more than one flight 
of ordinary stairs at a normal pace and in normal conditions.
III
Marked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing 
one flight of stairs in normal conditions and at normal pace.
IV
Inability to carry on any physical activity without discomfort, anginal syndrome may be present at rest.
Table I14
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 J
Concomitant Medications
J 1
Guidance Regarding Potential Interactions with Concomitant 
Medications
Throughout the study, participants should avoid changes to, or the addition of, all concomitant 
medications and, in particular, any that may affect the metabolism of selumetinib 
(eg, CYP2C19 or CYP3A4 moderate/strong inhibitors, as well as CYP3A4 moderate/strong 
inducers), unless considered clinically indicated. The use of any natural/herbal products or 
other “folk remedies” should be discouraged, but use of these products, as well as use of all 
vitamins, nutritional supplements, and all other concomitant medications must be recorded in 
the eCRF.
Strong or moderate inducers of CYP3A4 are not allowed at any time during the study. During 
the first cycle concomitant use of strong or moderate inhibitors of CYP3A4 or CYP2C19, 
with the exception of chronic PN pain medication, should be avoided until after the PK 
assessment. During the remainder of the study, if concomitant use of selumetinib with strong 
or moderate CYP3A4 or CYP2C19 inhibitors is not avoidable, then the selumetinib dose 
should be reduced as shown in Table J15. For chronic PN pain medication fulfilling the above 
criteria, selumetinib should be initiated at a reduced dose as shown in Table J15. The dose of 
selumetinib should be reduced for the duration of concomitant therapy with the strong or 
moderate CYP3A4 or 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.
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, furosemide
benzylpenicillin, baricitinib and tenofovir) cannot be excluded and they should be 
administered with caution.
Table J15
Recommended Dosage of Selumetinib for Co-administration with 
Strong or Moderate CYP2C19 or CYP3A4 Inhibitors
BSA (m2)
If the current dosage is up to 25 mg/m2
bid, reduce to 20 mg/m2 bid
If the current dosage is up to 20 mg/m2
bid, reduce to 15 mg/m2 bid
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
bid, twice daily; BSA, body surface area; CYP, cytochrome P450. 

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Changes to, or addition of medications detailed in Table J16 and Table J17 should be avoided, 
unless clinically indicated. The lists in Table J16 and Table J17 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 J16
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 bid a
Telapravir
stiripentol
Itraconazole
voriconazole
Ketoconazole
triclabendazole
Voriconazole
Cannabidiolb
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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Table J16
Inhibitors of CYP2C19 or CYP3A4 that AstraZeneca Recommends not 
to be Combined with Selumetinib
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 bid) 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.
bid, twice daily; CYP, cytochrome P450; QD, once daily.

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Table J17
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
Pexidartinib
Etravirine
Elagolix
Sotorasib
Telotristat ethyl
Nevirapine
CYP, cytochrome P450.
J 2
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted and prohibited concomitant medications/therapies are described in Table J18. Refer 
also to the dose modification guidelines for management of study intervention-related 
toxicities in Section 6.6.
Table J18
Restricted and Prohibited Medications/Therapies
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
Prior exposure is prohibited.
Not allowed during the study (with the exception of selumetinib study 
intervention).

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Table J18
Restricted and Prohibited Medications/Therapies
Prohibited medication/class of 
drug
Usage (including limits for duration permitted and special 
situations in which it is allowed)
Other systemic PN target treatment 
(including chemotherapy, 
immunotherapy, targeted therapy, 
biologic therapy, or monoclonal 
antibodies)
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 study 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 screening assessment.
Blood transfusion (red blood cells 
or other blood products)
Not allowed within the 28 days prior to screening assessment.
Multivitamins containing vitamin E
Must be stopped 7 days prior to initiation of study intervention.
Not allowed during the study.
Herbal supplements or medications 
known to be strong or moderate 
inhibitors or inducers of CYP3A4 
or strong or moderate inhibitors of 
CYP2C19. Substrates of OAT3.
Must be safely discontinued at least 14 days or 5 half-lives (whichever 
is longer) before the first dose of study intervention.
Strong or moderate inducers of CYP3A4 are not allowed at any time 
during the study. During the first cycle, concomitant use of strong or 
moderate inhibitors of CYP3A4 or CYP2C19 should be avoided until 
after the PK assessment. During the remainder of the study, if 
concomitant use of selumetinib with strong or moderate CYP3A4 or 
CYP2C19 inhibitors is not avoidable, then the selumetinib dose should 
be reduced as shown in Table J15. The dose of selumetinib should be 
reduced for the duration of concomitant therapy with the strong or 
moderate CYP3A4 or 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.
Selumetinib may affect the plasma/serum concentrations of substrates 
of OAT3 and they should be given with caution.
CYP, cytochrome p450; IMP, investigational medicinal product; MEK = mitogen activated protein kinase; 
OAT3, organic anion transporter 3; PN, plexiform neurofibroma.

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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 AstraZeneca 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 5.3 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 1 must be undertaken to confirm eligibility using the same randomisation 
number as for the participant.

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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 
(ie, 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 AstraZeneca-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.
Note: In Germany other non-PI tasks of HCP/TPV are not described in the CSP but in the 
main Local ICF Part I, Section 11-d (for example reaching out to patients to ask opinions on 
the Thank You card and Trial Result Summary, payment of patient expenses/compensation, 
optional telephone interview, management of accounts for Apps/devices, or in case of 
COVID-19 pandemic, possible additional services may be implemented e.g. drug courier 
services).

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Appendix L
Abbreviations
Abbreviation or Special 
Term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve 
AUC(0-6)
Area under the concentration-time curve from time 0 to 6 hours
AUC(0-8)
Area under the concentration-time curve from time 0 to 8 hours
AUC(0-12)
Area under the concentration-time curve from time 0 to 12 hours
AUClast
Area under the concentration-time curve from time 0 to the last quantifiable 
concentration
bid
Twice daily
BP
Blood pressure
BSA
Body surface area
CRF
Code of Federal Regulations
CI
Confidence interval
CK
Creatine kinase
CK-MB
Creatine kinase-myocardial band
CK-MM
Creatine kinase-muscle
CL/F 
Apparent total body clearance of the drug from plasma after extravascular 
administration
Cmax
Maximum observed concentration
COA
Clinical Outcome Assessment
CR
Complete response
CRO
Contract research organisation
CSP
Clinical study protocol
CSR
Central serous retinopathy
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trials Information System
CV
Coefficient of variation
CYP
Cytochrome P450
DCO
Data cut-off
DES
Data entry site
DILI
Drug-induced liver injury
DoR
Duration of response

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Abbreviation or Special 
Term
Explanation
e-Diary
Electronic diary
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
EoT
End of Treatment
ePRO
Electronic patient-reported outcomes
EQ-5D-5L
EuroQol 5-Dimension 5-level
EQ-VAS
EuroQol visual analogue scale
ERK
Extracellular signal-regulated kinase
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GRAD
Global Retention and Disposal Standard
GTPase
Guanosine 5'-triphosphatase
Hb
Haemoglobin
HCP
Health Care Professional
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
HRQoL
Health-related quality of life
IATA
International airline transportation association
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICR
Independent central review
IEC
Independent Ethics Committee
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

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Abbreviation or Special 
Term
Explanation
IRT
Interactive Response Technology
IT
Information technology
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LPD
Last participant dosed
LVEF
Left ventricular ejection fraction
LVSD
Left ventricular systolic dysfunction
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities;
MEK
Mitogen activated protein kinase
MMRM
Mixed model repeated measures
MPAUC
Metabolite: parent ratio based on AUC
MPCmax
Metabolite: parent ratio based on Cmax
MPNST
Malignant peripheral nerve sheath tumours
MRI
Magnetic resonance imaging
MTP
Multiple testing procedure
n
Number
NCI
National Cancer Institute
NE
Not evaluable
NF1
Neurofibromatosis type 1
NIH
National Institutes of Health
NIMP
Non investigational medicinal product
NRS-11
Numerical Rating Scale-11
OAT3
Organic anion transporter 3
ORR
Objective response rate
PAINS-pNF
PAin INtensity Scale for plexiform neurofibromas
PBMC
Peripheral blood mononuclear cells
PedsQL
Paediatric Quality of Life Inventory
PD
Progressive disease
pERK
Phosphorylated extracellular signal-regulated kinase
PFS
Progression free survival
PGIC
Patients Global Impression of Change
PGIS
Patients GLOBAL Impression of Severity
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)

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Abbreviation or Special 
Term
Explanation
PlexiQoL
Plexiform Neurofibroma Quality of Life scale
PN
Plexiform neurofibroma
PR
Partial response
PRO
Patient-Reported Outcomes
PROMIS
Patient-Reported Outcomes Measurement Information System
PT
Preferred term
PTT
Partial thromboplastin time
QTcF
QTc interval as corrected by Fridericia’s formula
REiNS
Response Evaluation in Neurofibromatosis and Schwannomatosis
RNA
Ribonucleic acid
RPED
Retinal Pigment Endothelial Detachment
RT-PCR
Reverse transcription polymerase chain reaction
RVO
Retinal vein occlusion
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SMQ
Standardised MedDRA query
SoA
Schedule of Activities
TBL
Total bilirubin
tlast
Time of last observed concentration
tmax
Time to reach maximum observed concentration following drug administration
TPV 
Third Party Vendor
TTP
Time to progression
TTR
Time to response
ULN
Upper limit of normal
US
United States
VAS
Visual analogue scale
VO2
Maximal oxygen uptake
Vss/F
Volume of distribution (apparent) at steady state after extravenous administration 
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 TOC. 
Amendment 1.0 (Version 2.0): (25 January 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 revise the primary objective to be comparative 
relative to placebo, as requested by the FDA. A consequence of this update is an increase in 
the duration of treatment prior to crossover from placebo to selumetinib. The interim analysis 
has been revised. 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.
Summary of Substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1, Synopsis, 
Section 3, Table 4, 
Objectives and 
Endpoints, Section 9.1, 
Statistical Hypotheses, 
Section 9.2, Sample 
Size Determination, 
Section 9.4, Statistical 
Analyses
Changed primary endpoint of ORR assessment to 
be a formal hypothesis test comparing selumetinib 
versus placebo.
Moved previous primary endpoint of single-arm 
ORR assessment of selumetinib to be a secondary 
endpoint.
Updates to statistical analyses sections including 
MTP to reflect change.
FDA recommendation
Section 1.1, Synopsis, 
Section 4.1, Overall 
Design, and throughout
Additional DCO added
Due to the revision of the 
interim analysis
Section 1.1, Synopsis, 
Section 4.1, Overall 
Design, and throughout
Increase duration of placebo-controlled period from 
8 cycles to 12 cycles
To allow robust comparison 
of ORR between treatment 
arms by end of Cycle 16 
landmark

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1, Synopsis, 
Section 4.1, Overall
Design, Section 4.2
Scientific Rationale for 
Study Design 
Section 9.1, Statistical 
Hypotheses, 
Section 9.4.2.1.3
Analysis Methods
Timing of primary analysis changed from 
12 months post LPD to landmark analysis by end of 
16 cycles
At least 16 cycles of follow 
up is required to perform a 
meaningful comparison of 
ORR on selumetinib vs 
placebo
Section 1.3, Schedule 
of Assessments, 
Table 1 and Table 2
Additional timepoints for PGIS/PGIC, investigator 
assessment of changes in pain medication, AEs, and 
concomitant mediations added
Due to increased duration of 
placebo-controlled period
Section 1.3, Schedule 
of Assessments, 
Table 1 and 
Section 8.2.6, Clinical 
Safety Laboratory 
Assessments
Pregnancy tests changed to every cycle throughout, 
instead of at each visit
Study population is adults 
including women of child-
bearing potential, which 
differs from previous studies 
that were carried out in a 
paediatric population
Section 1.1, Synopsis, 
Section 4.1, Overall 
Design, Section 9.2, 
Sample Size 
determination 
Added that if it is anticipated that 20% or more of 
participants withdraw prior to the end of Cycle 16 , 
for reasons other than progression, then recruitment 
rates withstanding, enrolment will continue to 
randomise at least 50% of the total number of drop-
out participants
To ensure the primary 
endpoint is adequately 
powered
Section 5.1, Inclusion 
Criterion 2
Updated NF1 diagnostic criteria
To align with the most 
recent published guidance 
(Legius et al 2021)
Section 9.5, Interim 
Analyses
Amended interim analysis
To provide earlier data with 
good power on the primary 
and key secondary endpoint
AE, adverse event; DCO, Data cut-off; FDA, Food and Drug Administration; LPD, Last participant dosed; 
NF1, Neurofibromatosis type 1; ORR, Objective response rate; MTP, Multiple testing procedure; PGIC, Patients 
Global Impression of Change; PGIS, Patients GLOBAL Impression of Severity.

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Summary of Non-substantial Changes
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3, Schedule 
of Assessments, 
Table 1
Footnote ‘o’: Added that all volumetric MRI scans 
should be performed relative to Cycle 1 Day 1, ie the 
time course should not change if the participant 
experiences a dose interruption or there are delays in 
previous scan visits
Footnote ‘e’ amended to add results of any previous 
genetic testing for NF1 to disease characteristics.
Updated general footnote to state “Participant's second 
dose on the day of their on-site visit can be taken from 
newly dispensed study intervention”
Clarification
Section 1.1, Synopsis, 
Section 3, Table 4, 
Objectives and 
Endpoints
Added that measurable target PN at baseline is per ICR 
and clarified analysis populations
Clarification
Section 1.1, Synopsis, 
Section 3, Table 4, 
Objectives and 
Endpoints
Added PFS evaluation during the randomised period as
an exploratory endpoint
For additional 
information
Section 1.1, Synopsis, 
Section 3, Table 4, 
Objectives and 
Endpoints
Removal of "as assessed by the investigator" for the 
exploratory objective of long-term assessment of pain 
medication compared to baseline
Assessment not relevant 
as data are only collected 
during the randomised 
period
Section 1.1 Synopsis, 
Section 3, Table 4, 
Objectives and 
Endpoints
Added an exploratory objective to investigate NF1 
mutation alteration patterns
For additional 
information
Section 2.2
Background and 
Section 8.1.8.1 PAINS-
pNF
Added definition for chronic PN pain and spikes of PN 
pain
Clarification
Section 4.1, Overall 
Design
Final analysis wording changed from 24 months post 
LPD to 24 cycles post LPD
Clarification
Section 5.2, Exclusion 
Criterion 3
Updated optic glioma criterion
Clarification
Section 5.2, Exclusion 
Criterion 12
Clarified that prosthesis or orthopaedic or dental braces 
should not be in close proximity to the area of interest 
Clarification
Section 5.2, Exclusion 
Criterion 17
Corrected restriction of CYP2C19 inducers
Clarification
Section 5.3, Screen 
Failures
Clarified that participants can be rescreened if failure 
was for a technical reason and amended wording 
describing reason for withdrawal to match eCRF
Clarification

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1, Synopsis, 
Section 4.1, Overall 
Design, Section 6.1.1, 
Investigational 
Products
Clarified that following crossover to selumetinib 
treatment, treatment will be open-label
Clarification
Section 1.1, Synopsis, 
Section 6.1.1, 
Investigational 
Products
Clarification that unblinded open label stock will be 
dispensed to the participant following crossover added
Clarification
Section 6.1.1, 
Investigational 
Products
Guidance provided for when a dose is missed or if 
vomiting occurs
To provide guidance
Section 6.3, Measures 
to Minimise Bias: 
Randomisation and 
Blinding, Section 7.2, 
Participant Withdrawal 
from the Study
Clarification that emergency unblinding leads to 
discontinuation from the study
Clarification
Section 6.5, 
Concomitant Therapy 
Appendix J, 
Concomitant 
Medication
Removed the restriction for CYP2C19 inducers, 
updated the guidance for CYP2C19 inhibitors as well 
as the lists of example inhibitors and inducers
To correct an error and 
provide most recent 
guidance
Section 6.5, 
Concomitant Therapy 
Appendix J, 
Concomitant 
Medication
Included guidance on substrates of OAT3
Although selumetinib 
does not meet the criteria 
for OAT3 inhibition 
according to FDA 
guidance, it does for
European Medicines 
Agency guidance
Section 8.1.1 Imaging 
of the Target PN, 
Section 8.1.2
Independent Central 
Review of Scans, 
Section 9.4.2.1.1
Calculation of PN 
Assessment
Included additional guidance on MRI scans 
(Section 8.1.1) and removed reference to Independent 
Review Charter
Document not relevant to 
Investigator
Section 8.1.8.9, 
Administration of 
ePRO Questionnaires
Added that paper questionnaires are allowed in 
exceptional circumstances
To allow a back-up 
process if required

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Section Number and 
Name
Description of Change
Brief Rationale
Section 8.1.8.10
Qualitative Participant 
Interviews
Updated number of participants
Update
Section 8.2.6 Clinical 
Safety Laboratory 
Assessments, Table 8
Updated footnote to clarify reporting of aPTT and PTT 
tests and added footnotes to clarify reporting of 
leukocyte differential count (absolute count) urea 
nitrogen and blood urea nitrogen
Clarification
Section 8.3.2, Follow-
up of AEs and SAEs
Clarified information collected on grade of AEs
Clarification
Section 9.3, 
Populations for 
Analysis
Updates to populations to reflect change in primary 
objective, to include Measurable PN FAS analysis 
population and to clarify analysis populations
Clarification
Section 9.4.1, General 
Considerations
Added definition of randomised period
Clarification
Section 9.4.2.2, Key 
Secondary Endpoint
Geographical region added as a baseline covariate and 
clarified chronic pain medication use is based on 
e-Diary and investigator’s assessment of pain 
medication
Clarification
Section 1.1, Synopsis, 
Section 9.4.2.2, Key 
Secondary Endpoint, 
Section 9.4.2.3.7
Chronic Target PN 
Pain Palliation
Clarified that average cycle PAINS-pNF chronic target 
pain score will only be derived if the participant meets 
the criteria of having at least 4 daily pain scores out of 
7 days for at least 3 non-overlapping 7-day periods in 
the 28-day cycle
Clarification
Section 9.4.2.3
Secondary Endpoints
Clarified populations for analysis
Clarification
Section 9.4.2.3.2, 
Duration of Response, 
Section 9.4.2.3.4, Time 
to Progression, 
Section 9.4.2.3.5, Time 
to Response, 
Section 9.4.2.3.6, Best 
Percentage Change 
from Baseline in Target 
PN
Clarified that the analysis will include all participants 
randomised to study intervention with measurable 
target PN at baseline per ICR.
Clarification
Section 9.4.3.1
Adverse Events
Removed “High level term” from the presentation of 
AEs
Not standard
Section 9.4.3.5 Other 
Safety Endpoint(s)
Removed summarisation of physical examination data
Not required

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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, 
Section 9.4.4.1
Pharmacokinetics, 
Section 3, Table 4, 
Objectives and 
Endpoints
Aligned description of PK parameters to AstraZeneca 
standards and SAP and removed detailed descriptions 
included in SAP
Clarification
Appendix G3
PROMIS Item Bank updated
Correction
Throughout protocol
PAIN-pNF amended to PAINS-pNF (PAin INtensity 
Scale for plexiform neurofibromas).  
Renaming of the 
PAIN-pNF tool by the 
NCI
AE, adverse event; aPTT, Activated partial thromboplastin time; eCRF, Electronic case report form; FAS, Full 
Analysis Set; FDA, Food and Drug Administration; ICR, Independent central review; LPD, Last participant dosed; 
MRI, Magnetic resonance imaging; NF1, Neurofibromatosis type 1; PAINS-pNF, PAin INtensity Scale for 
plexiform neurofibromas; PK, Pharmacokinetics; PFS, Progression free survival; PN, Plexiform neurofibroma; 
PROMIS, Patient-Reported Outcomes Measurement Information System; PTT, Partial thromboplastin time; 
SAP, statistical analysis plan.

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Appendix N
Country Specific Requirements
European Union Country Specific Requirements
Section # and Name
Description of Change with Reason
Section 4.5 Study Conduct Mitigation 
during Study Disruptions due to Cases of 
Civil Crisis, Natural Disaster, or Public 
Health
In accordance with Local Regulatory Authority 
requirements, it’s specified that in Germany 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) there will be 
no verbal consenting.
Consent is obtained in writing
Appendix K Changes Related to 
Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or 
Public Health Crisis
In accordance with Local Regulatory Authority 
requirements, it’s specified that in Germany 
other non-PI tasks of HCP/TPV are not 
described in the CSP but in the main Local ICF 
Part I, Section 11-d (reach out to patients to ask 
opinion for Thank You card and Trial Result 
Summary, payment of patient 
expenses/compensation, optional telephone 
interview, manage accounts for Apps/devices, or 
in case of COVID-19 pandemic, possible 
services may be implemented e.g. drug courier 
services).
Section 8.3.9. Deaths
Section 8.3.12 Reporting of Serious 
Adverse Events
Section 8.3.14.1 Timelines
Section 8.4 Overdose
In Germany SAE reporting has to be done 
immediately without undue delay after obtaining 
knowledge.

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11
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