Pembrolizumab and Hypofractionated Stereotactic Radiotherapy in Patients With Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Advanced Malignant Pleural Mesothelioma
Sponsor: Royal Marsden NHS Foundation Trust

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 ....................................................................................................................... 11 
1 
Trial Summary ................................................................................................................................ 12 
2 
BACKGROUND & RATIONALE .......................................................................................................... 16 
2.1 
Background ........................................................................................................................................ 16 
2.2 
Chemotherapy for patients with resectable MPM ................................................................................ 16 
2.2.1 
First-line chemotherapy for unresectable MPM ........................................................................................................ 16 
2.2.2 
Second-line chemotherapy for unresectable MPM ................................................................................................... 17 
2.2.3 
Immune Evasion in Cancer ......................................................................................................................................... 18 
2.2.4 
Targeting the PD-1/PD-L1 axis .................................................................................................................................... 18 
2.2.5 
Rationale for combining anti-PD-1 effects with radiation .......................................................................................... 20 
2.2.6 
Pembrolizumab Clinical Trial Data .............................................................................................................................. 22 
2.2.6.1 
Pembrolizumab ................................................................................................................................................. 22 
2.2.6.2 
Clinical Trial Data .............................................................................................................................................. 22 
2.3 
Rationale for the Trial ......................................................................................................................... 22 
3 
Study OBJECTIVES & Endpoints ....................................................................................................... 24 
3.1 
Study Objectives & Hypothesis ............................................................................................................ 24 
3.1.1 
Primary Objective & Hypothesis ................................................................................................................................. 24 
3.1.2 
Secondary Objectives ................................................................................................................................................. 24 
3.1.3 
Exploratory Objectives ............................................................................................................................................... 24 
3.2 
Study Endpoints .................................................................................................................................. 24 
3.2.1 
Primary Endpoint ........................................................................................................................................................ 24 
3.2.2 
Secondary Endpoints .................................................................................................................................................. 24 
3.2.3 
Exploratory Endpoints ................................................................................................................................................ 24 
4 
Study DESIGN ................................................................................................................................. 25 
4.1 
Summary of Study Design ................................................................................................................... 25 
4.2 
Treatment Regimen ............................................................................................................................ 25 
4.2.1 
Dose Limiting Toxicities .............................................................................................................................................. 26 
4.3 
Study Schema ..................................................................................................................................... 27 
4.4 
Follow-Up after stopping Pembrolizumab ............................................................................................ 27 
4.4.1 
30 Day Safety Follow-Up Visit ..................................................................................................................................... 27 
4.4.2 
Follow-Up for Discontinued Pembrolizumab without Disease Progression ............................................................... 27 
4.4.3 
Survival Status Follow-Up Phase ................................................................................................................................ 28 
4.5 
Study Termination .............................................................................................................................. 28 
4.5.1 
Clinical Criteria for Early Trial Termination ................................................................................................................. 28 
4.6 
Treatment after End of Study .............................................................................................................. 28 
5 
Selection of Patients ....................................................................................................................... 29 

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5.1 
Screening and Enrolment .................................................................................................................... 29 
5.2 
Registration ........................................................................................................................................ 29 
5.3 
Patient Replacement Strategy ............................................................................................................. 29 
5.4 
Entry Criteria ...................................................................................................................................... 30 
5.4.1 
Inclusion criteria ......................................................................................................................................................... 30 
5.4.2 
Exclusion Criteria ........................................................................................................................................................ 31 
6 
Study Plan and procedures ............................................................................................................. 33 
6.1 
Study Schedule ................................................................................................................................... 33 
6.2 
Administrative Procedures/Assessments ............................................................................................. 36 
6.2.1 
Informed Consent ....................................................................................................................................................... 36 
6.2.2 
Inclusion/Exclusion Criteria ........................................................................................................................................ 36 
6.2.3 
Demographic Data, Medical History and Treatment History ..................................................................................... 37 
6.2.4 
Subsequent Anti-Cancer Therapy Status .................................................................................................................... 37 
6.2.5 
Survival Status ............................................................................................................................................................ 37 
6.2.6 
Prior and Concomitant Medications Review .............................................................................................................. 37 
6.2.6.1 
Prior Medications .............................................................................................................................................. 37 
6.2.6.2 
Concomitant Medications ................................................................................................................................. 37 
6.3 
Clinical Procedures/Assessments ........................................................................................................ 38 
6.3.1 
PD-L1 Assessment ...................................................................................................................................................... 38 
6.3.2 
Adverse Event (AE) Monitoring .................................................................................................................................. 38 
6.3.3 
MRC dyspnoea Score .................................................................................................................................................. 38 
6.3.4 
Full Physical Exam ....................................................................................................................................................... 38 
6.3.5 
Directed Physical Exam ............................................................................................................................................... 38 
6.3.6 
Vital Signs ................................................................................................................................................................... 39 
6.3.7 
Eastern Cooperative Oncology Group (ECOG) Performance Scale............................................................................. 39 
6.3.8 
Pulmonary Function Tests .......................................................................................................................................... 39 
6.3.9 
Pregnancy Tests .......................................................................................................................................................... 39 
6.3.10 
Haematology, Biochemistry and Urinalysis (including, β-hCG†, PT, aPTT, fT3, fT4 and TSH) ................................ 39 
6.3.11 
Tumour Imaging and Assessment of Disease ........................................................................................................ 40 
6.3.11.1 
Baseline tumour imaging .................................................................................................................................. 40 
6.3.11.2 
Timing of Disease Assessment .......................................................................................................................... 40 
6.3.11.3 
Confirmation of Disease Response ................................................................................................................... 41 
6.3.11.4 
Confirmation of Disease Progression ................................................................................................................ 42 
6.3.12 
Tumour Tissue Collection and Correlative Studies Blood Sampling ...................................................................... 42 
6.3.12.1 
Archival Tumour tissue samples ....................................................................................................................... 42 
6.3.13 
Tumour Biopsies and Research Blood Samples ..................................................................................................... 43 
6.3.14 
Chain of Custody of Biological Samples ................................................................................................................. 43 
6.4 
Total Blood Volume ............................................................................................................................ 43 
7 
Treatments .................................................................................................................................... 44 
7.1 
SBRT for pleural mesothelioma ........................................................................................................... 44 
7.1.1 
Planning and Delivery ................................................................................................................................................. 44 
7.1.2 
Toxicity Assessments .................................................................................................................................................. 44 
7.2 
Pembrolizumab .................................................................................................................................. 44 
7.2.1 
Investigational Product ............................................................................................................................................... 44 
7.2.2 
Product Preparation ................................................................................................................................................... 44 
7.2.3 
Storage and Handling ................................................................................................................................................. 44 
7.2.3.1 
Storage .............................................................................................................................................................. 44 
7.2.3.2 
Handling ............................................................................................................................................................ 44 
7.2.4 
Packaging and Labelling Information ......................................................................................................................... 45 
7.2.5 
Returns and Reconciliation ......................................................................................................................................... 45 

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7.2.6 
Doses and Treatment Regimens ................................................................................................................................. 45 
7.2.7 
Timing of Dose Administration ................................................................................................................................... 46 
7.2.8 
Blinding/Masking ........................................................................................................................................................ 46 
7.2.9 
Dose Selection/Modification ...................................................................................................................................... 46 
7.2.9.1 
Dose Selection ................................................................................................................................................... 46 
7.2.9.2 
Dose Modification ............................................................................................................................................. 47 
7.3 
Concomitant medications ................................................................................................................... 49 
7.3.1 
Prohibited Concomitant Medications ........................................................................................................................ 49 
7.3.2 
Acceptable Concomitant Medications ....................................................................................................................... 50 
7.4 
Rescue Medications & Supportive Care ............................................................................................... 50 
7.4.1 
Supportive Care Guidelines ........................................................................................................................................ 50 
7.4.1.1 
Diarrhoea .......................................................................................................................................................... 50 
7.4.1.2 
Nausea/vomiting ............................................................................................................................................... 51 
7.4.1.3 
Infection ............................................................................................................................................................ 51 
7.4.1.4 
Immune-related adverse events ....................................................................................................................... 51 
7.4.1.5 
Management of infusion reactions ................................................................................................................... 52 
7.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related Events of 
Clinical Interest (irECI) ..................................................................................................................................... 52 
7.6 
Supportive Care Guidelines for Pneumonitis ........................................................................................ 56 
7.7 
Diet/Activity/Other Considerations ..................................................................................................... 57 
7.7.1 
Diet ............................................................................................................................................................................. 57 
7.7.2 
Contraception ............................................................................................................................................................. 57 
7.7.3 
Use in Pregnancy ........................................................................................................................................................ 58 
7.7.4 
Use in Nursing Women ............................................................................................................................................... 58 
7.7.5 
Treatment of Overdose of IMP ................................................................................................................................... 58 
7.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study .................................. 58 
7.8.1 
Permanent Discontinuation of Trial Medication ........................................................................................................ 58 
7.9 
Withdrawal from the Study ................................................................................................................. 59 
8 
Pharmacovigilance ......................................................................................................................... 61 
8.1 
Adverse events ................................................................................................................................... 61 
8.1.1 
Adverse Event Definition ............................................................................................................................................ 61 
8.1.2 
Adverse Reaction Definition ....................................................................................................................................... 61 
8.1.3 
Disease Progression .................................................................................................................................................... 61 
8.1.4 
New Cancers ............................................................................................................................................................... 61 
8.1.5 
Abnormal Laboratory Test Results ............................................................................................................................. 61 
8.1.6 
Pregnancy and Lactation ............................................................................................................................................ 62 
8.2 
Assessing and Recording Adverse Events ............................................................................................. 62 
8.3 
Evaluating Adverse Events .................................................................................................................. 62 
8.3.1 
Determining AE Severity and Grade ........................................................................................................................... 63 
8.3.2 
Determining AE Causality ........................................................................................................................................... 63 
8.4 
Serious adverse events (SAEs) ............................................................................................................. 63 
8.4.1 
Reporting SAEs ........................................................................................................................................................... 64 
8.4.2 
Events exempt from being reported as SAEs ............................................................................................................. 65 
8.4.3 
Determining SAE Causality and Expectedness ........................................................................................................... 65 
8.5 
Events of Clinical Interest .................................................................................................................... 65 
8.5.1 
Definitions of Evidence of Clinical Interest (ECI) ........................................................................................................ 65 
8.5.2 
Reporting of ECIs ........................................................................................................................................................ 66 
8.6 
Definition of an Overdose for this Protocol and Reporting of Overdose ................................................ 68 

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8.7 
Reporting of Pregnancy and Lactation ................................................................................................. 68 
8.8 
Definition of a Serious Adverse Reaction (SAR) .................................................................................... 69 
8.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) ......................................... 69 
8.10 
Reporting of SUSARs ........................................................................................................................... 69 
8.11 
Annual Reporting of Serious Adverse Events........................................................................................ 69 
8.12 
Urgent Safety Measures ...................................................................................................................... 70 
9 
Data analysis and statistical considerations .................................................................................... 71 
9.1 
Statistical Analyses ............................................................................................................................. 71 
9.1.1 
Primary Endpoint ........................................................................................................................................................ 71 
9.1.2 
Secondary Endpoints .................................................................................................................................................. 71 
9.1.3 
Exploratory Endpoints ................................................................................................................................................ 72 
9.1.4 
Timing of analyses ...................................................................................................................................................... 72 
9.2 
Sample Size ........................................................................................................................................ 72 
10 Regulatory, Ethical and Legal Issues ............................................................................................... 73 
10.1 
Good Clinical Practice ......................................................................................................................... 73 
10.2 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) ............................................... 73 
10.3 
Annual Safety Reports and End of Trial Notification ............................................................................. 73 
10.4 
Regulatory Authority Approval ............................................................................................................ 73 
10.5 
Notifications of Serious Breaches to GCP and/or the Protocol .............................................................. 74 
10.6 
Insurance and Liability ........................................................................................................................ 74 
10.7 
Contact with General Practitioner (GP) ................................................................................................ 74 
10.8 
Confidentiality .................................................................................................................................... 74 
10.9 
Data Collection and Documentation .................................................................................................... 75 
10.10 End of Trial ......................................................................................................................................... 75 
11 Data and study management ......................................................................................................... 76 
11.1 
Source Data ........................................................................................................................................ 76 
11.2 
Language ............................................................................................................................................ 76 
11.3 
Data Collection ................................................................................................................................... 76 
11.4 
Recording of Data ............................................................................................................................... 76 
11.5 
Data Management .............................................................................................................................. 77 
11.6 
Study Management Structure ............................................................................................................. 77 
11.6.1 
Delegations of Responsibilities .............................................................................................................................. 77 
11.6.1.1 
RM-CTU ............................................................................................................................................................. 77 
11.6.1.2 
MSD ................................................................................................................................................................... 77 
11.6.1.3 
Participating Sites ............................................................................................................................................. 77 
11.7 
Protocol Compliance and Amendments ............................................................................................... 78 
11.8 
Trial Management .............................................................................................................................. 78 
11.9 
Safety Review Committee (SRC) .......................................................................................................... 78 
11.10 Monitoring ......................................................................................................................................... 79 

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11.11 Quality Control and Quality Assurance ................................................................................................ 79 
11.12 Clinical Study Report ........................................................................................................................... 79 
11.13 Record Retention ................................................................................................................................ 79 
11.14 Reporting and Publication ................................................................................................................... 80 
12 APPENDICES ................................................................................................................................... 81 
12.1 
Appendix 1 – ECOG Performance status............................................................................................... 81 
12.2 
Appendix 2 – MRC Dyspnoea scale ...................................................................................................... 82 
12.3 
Appendix 3 – Radiotherapy Planning and Delivery Guidelines .............................................................. 83 
12.4 
Appendix 4 - Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ....................................... 87 
12.5 
Appendix 5 - Identification, Evaluation and Management of immune related events of clinical interest 
(irECIs) 88 
12.6 
Appendix 6 – Modified Response Evaluation Criteria in Solid Tumours (mRECIST) Criteria for Evaluating 
Response in Malignant Pleural Mesothelioma ................................................................................................. 94 
13 References ..................................................................................................................................... 95 
	

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#
Fractions
AE
Adverse events
ALK
Anaplastic lymphoma kinase gene
ALT
Alanine transaminase
ANC
Absolute neutrophil count
APC
Antigen presenting cell
APTT
Activated partial thromboplastin time 
AST
Aspartate transaminase
ATP
Adenosine triphosphate 
C
Cycle 
CD
Cluster differentiation
CI
Chief Investigator
CNS
Central nervous system
CR 

-2	2
CRFs
Case Report Forms
CT 
Computerised tomography
CTA

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CTCAE
Common Toxicity Criteria for Adverse Events 
ctDNA
Circulating tumour deoxyribonucleic acid
CTLA-4
Cytotoxic T-lymphocyte antigen-4
D
Day
DCR
Disease control rate
DLT
Dose limiting toxicity
DOR
#	"	2
DSUR
*2-	"1	92	2	
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor gene
FDA
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FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
Gy 
Gray
HIV
Human immunodeficiency virus
HMGB1 
High-mobility group protein B1
HR 
0/	
i.v. 
Intravenous
IB
Investigator’s Brochure
ID
Identification
IEC
2	3	
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IL
Interleukin
IMP
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IR 
)	
irAE
Immune-related adverse events
IRD
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irECI
Immune-related events of clinical interest 

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Immune-related response criteria
ITIM
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ITSM
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Kg
Kilogram
L 
Litre
MAD
Maximum administered dose
mg 
Milligram
MHC
Major histocompatibility complex
MHRA
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mmol 
Millimoles
MRC
Medical Research Council
MSD
Merck Sharp & Dohme  
MTD
Maximum tolerated dose
NCI 
National Cancer Institute
NCRI CTRad 
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NK
Natural killer cells
ORR
Overall response rate
OS 
Overall survival 
PD 
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PD-1
Programmed cell death protein 1 
PD-L1
Programmed death ligand-1
PD-L2
Programmed death ligand-2
PFS
Progression free survival 
PI 
Principal Investigator
PR
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PT
Prothrombin time
QA
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QC
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RDSU
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REC
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RECIST
Response evaluation criteria in solid tumours 
RM-CTU
Royal Marsden Clinical Trials Unit
RP2D
Recommended phase 2 dose
SAE
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SBRT
Stereotactic body radiotherapy  
SD 
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SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
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SRS
Stereotactic radiosurgery 
STAT-3
Signal transducer and activator of transcription 3
SUSAR
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TIL
Tumour infiltrating lymphocytes
TLCO
Carbon monoxide transfer factor
TPS
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UK 
United Kingdom 
ULN 
Upper limit of normal 
USM
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¶Female of childbearing 
potential is defined as women 
following menarche and until 
becoming post-menopausal 
unless permanently sterile. 
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include hysterectomy, bilateral 
salpingectomy and bilateral 
oophorectomy. 
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#1
	

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2 
BACKGROUND & RATIONALE 
2.1 
Background 
)	 2#	 -3-	 :;	 	 	 	 #	 	 3	 #	 -1	 	 "	
#2	=2#		.<	34*	-	2	43#	C4	.	=2#	4	*2	
	:;		3	9	F)-<		<	3	)		"	'!!	2			22#	
	 3	 )	 -1	 	 "	 (	 2	 	 	 22#	 "	 	 :;	 	 --1	
-3-		*	"-	3	-3	#	)	3	2#<	.#				"-	3	2#-<	
2#-<	 	 #	 *)	 :;	 3	 	 3	 2-1	3)	 #.12	 "	 <	23<	
-<		.23	:	-=;<	43	23	3)1	.)	3	-	--	:;			
2.2 
Chemotherapy for patients with resectable MPM  
5	2	43	2.		43#	)"	-.<	#)	2	#	=2#	
2#--1		2#-1			)#		23			3*	-	
3	".1	"	-#-1	321		3	."	"	2622*	3-321		#"	: ;		
	 43	 #.	 	 	 -	 <	 43#	 )"	 -.<	 	 )	
2"-	#<	3#	.		"	1-	-	3	1-	-	"			#	
2	3	-	#3)		<	43	-	3			2)		1	4	-	.)	
22*	"	3		3		)	*	"	"		2*	3-321<	34*<		"-	
*	#22)	3		"	2*	3-321		3		)		
2.2.1 First-line chemotherapy for unresectable MPM 

1=	3-321	-		"	3	"4	32#	2	3	-2*	#**		2	43	
#.		-		-			3	2*	O-23	P	-	
3	3	-.	"	2		2-=	)*		3	-3	#**	."	*	2	<	
-2*)	-	#**	"-	(			-3	:Q;		2	43	#.		:';	+	-	
#**	."	4		43	3		"	=		2<	43	#**	)	"-	!!			
-3<	3#)3	.,*	)	2		4	4	-2	43	2		2-=	
:&;	?3	3	"	3		#		-2	-	"	.	#22*	<	3	>3		#1	
	 -	 2	 	 *	 1-2-	 	 :+
;	 43	 	 43#	 3	 *.	 	 	
:--1	 
<	 *.<	 	 2;	 :!;	 3	 	 #	 21<	 	 "	 )	 1<	 .3	
3-321	-	4	-.	"	1	"	3	2-1	2R		#**	."	4		*	
"	3	-.	3-321	-	-2	43	+
	:0	!(R	Q(;	$*3<	43	3	4	
-	4	1	21<	3	4		#.	""	.4	3-	43		)"	
		4	-3	#**	."	"	*.	*	+
	:0	!<	Q!;<	43				)*		
)	"	."	:0((<	Q( ;	+3#)3			3	-		."	"	2#-			

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
"	*	#22*	<	3	4)3	"	*	#))	3		*	2#-.	-.		C1	
	)*		."	"			3	-3	*	.	#22*			
	3	.	"	3	<	3	-.	"	2		2-=	3	.-		"	321	
44	"	2	43			#.	"	))*	#)1			43-	3-321		--	
	 2	 "	 	 -#-1	 )-	 
.2	 	 "	 #.#	 "	 2<	 #	 	 3	
-	 	 	 22	 "	 	 =1	 +3#)3	 3	 #	 "	 .2	 	 	 #22	 .1	
-	*<		3	3	.		-2	.4	3	4	2#-	)<	23				
#	3*	-	-	*1	"	3	.2		2	43	2-=<	43	.,*	
)	2		.4	M		M	:(<	;		-21<	3#)3		=2		
2)-	34		)31	4	2		"	.2.	321<		1	#**		-		
2)	4	*1	-	:;		)	4	#.#	.2	"	2		3	.	"	
	,#)-<	"	=-2	43	2	3*			2		
2.2.2 Second-line chemotherapy for unresectable MPM  
+"		3-321<		))*	-#-1	321<	2	-	*.1	=2		
#		2)	1	2	4	.	"	"<		-1	4<		3-321		3	2	
3	1	-				3	)	34)		-2*-		2)	"	#**	:5;	
4	#C	."	3	42	#	"	2-=		"	-	3	#1	-2	
	 2-=	 *#	 .	 #22*	 <	 43	 	 )"1	 3)3	 	 "	 2	 2<	 	
<		)	5		3	)#2	*)	2-=	:;	04*<	3			-		)	
3	#	"	2-=		-	"4)	"	#	$*3<			2*	*4	"	
	3-321	"#	3			43		321	4	.		3	2	
43	*	2-=<		3	43		2)	-		2)	:	-3;	"	"	321	
:;	5#3-<	2		43		2#-2-=	-.	3		4	C	"	3	
3	3		43	2-=		:0Q<	K;<	3#)3	3	.*	-1	.	"#	
.1		.		3	-	-2<	43	"	2	21	-	C1		*	
-.	321	)3<	3	#))	3	-	43	2-=		2#-			.	
2	"		321		"	2	43	2*#			"	2-=.	-		
+	*1	"	1=	)	3*	-	*1			-<	.#		3*	3	3	222	
-		)		"1	)#			3	1	2#	)		3	.	3	
3	C	"	-	)		-	3	4			C4	"	#**	."	#	"-	)	43	
-	.,*	)	2		3		)	3				3	##-		3	
)	"	-			"	*	)%	43	2	--1	*	"".	
	 321<	 3	 	 3	 22*	 .1	 )#1	 #3<	 	 <	 -C)	 3	 3	 "	
3-321	#)		2.			-2	-	2		.	)	)	*.	3		2	
	:;	"	'M		*	#**	"	('	-3			:;	
-.	"	)-.		

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								

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#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
*.	:	M<		(	-3<	5	!	-3;	: ;<	)-.		2#.	:M<		(	
-3<	5	'	-3			3)3		)#2;	:';<	<	2<		--1	
	:	M<		&	
-3<	5	&	-3;	:&;		3	3*	.	2		.<	3	.1		2		
	)	)	*.	3	.	"*#		2				22		-	"		4	)	
"			3		)			4)	"		4	)<	433		-	.3	
2		#**	."			-				
2.2.3 Immune Evasion in Cancer 
3	-2	"		--#	#*		)	#)43	"	2	"-	3	.	
C4	"		:!;		+#-#)	*	34			.4	#-#")	1-231	
:7;			#		"*#.	2)		*#	-)	:(;			2#	3	2	
"	
!S			3		"	
!S	""		6	5=S	)#1		-			43	
-2*	2)		)-	#**		-1		#-#	
			""*1	*	3	--#	1-<	#-#		-21		*1	"	-3-	+		
--#)	2		#-#			#	3#)3	3		--#	1-	"	=-2	3#)3	
#	C	:$F;		-	1	:<	 ;	3	--#	1-	-1	3	*2		2*	--#	
2	G#)	-2	1=			3		-	3#)3	3	0
	1-	+)	2)	
	:+
;	2#	#-#	)	2-)	3-					)	1-23		+"	2-)<			
			3	#		-)		#-#	#	43	31	"	#-#	2"	)		
""	 	 ""	 	 	 3	 2	 	 	 )	 "-	 3	 	 	 2	 	 *	 
-#1		3.1	-#	04*	-1	#-#		.		#			)1	:';	
	
3	--#	3C2	2341				2		#	-		3#)3	-2=	2	
)#	""			2	+-)	3	-2	"	3	2341		1=	1-231	)
	
7+	433		=2		3		#"	"		1=					.-	*	4)	.)	
43	>&		>&		3	+
	C2)	1=	*1		3C		
+3	C1	-2	"	3	2341		3	67	--#	3C2	2341	3		2
)				-,	2341	3,C	.1	#-#		#22	--#			3	-	"#	
"	<	=2		3		#"	"	*		#	331	<			4-#	
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2.2.4 Targeting the PD-1/PD-L1 axis 
	:	.1	3	)	;			)	#2"-1	--.			
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7;	:<	 ;		3	##	"	-#		3	.	*	:&;				"-1	--.		12		
--.	)12	)		)	.12	:12;	-	2.	"	)	.)	

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	 --#2	 1.	 43	 -"	 :;	 	 54)	 	 -#<	 	 #	 3	
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--.	2	)	.3	)		)
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	 *	 ))	 3#)3	 3	 	 2	 	 7	 	 =2	 	 4	 *	 	 *#	 
3-2	 #<	 -	 .1	 	 *#	 3#-<	 43	 7	 2	 	 1	 .1	
=2		)2)		"#		1-23	#		3	"--1	*-		
7	 	 3#)3	 	 	 --#	 	 *	 	 1-23	 )<	 43	 7	 *	 	 -2	
#4		"#		223	#	:;			
	
+3#)3	 331	 )	 =2	 	 :"	 1;	 7<	 	 *1	 "	 	 4	 -	 	 =2	
.#	*	"	3		3.		+.-	=2	"	7	4	"		&M	"	2	
43				#1	3	#1	C		(	2<	43	&&	3	#	*.	"	1	5-
"=	2""	-.	#<		43	7	:	7$;	)	4		2*	"	
LM	"	#-#		=2	7	"	3	-2			.)	2*<		3	--.#	)<	
'	 3	 12-	 )<	 	 	 3	 )	 	 3	 7	 7	 2*1	 	 -	 --	 	 
23	 3)1	 :& M;	 -2	 23	 3)1	 :M;	 7	 =2	 	 	 	 2	
2)	"	"	<	43	7	2*	2	3*)	-		"	&(	-3<	-2	43	
'	-3		7	)*	2	:!;	-1<	3	1	
	C		'	2	-2		
1	3-	"	7	=2	#)	--#33-1		55	#)		7	.1	
:	 0+;	*1	4	"		L M	--.#	6	12-	)	9)	3	-3<	
7	=2	4			M	"		+	-2	43	-	3)1	=2	7			
-2	#.12	+)<	7	=2	4		2	2)	"	"	<	437	2*	
2	3*)		-		"	 	-3<	-2	43	 	-3		7	)*	2	7	
=2	4		2	C	"	"	#**<	2	"	3)	)	:	&;	:(;	
	

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''&		+	,	%	&!	
)		"	((	
 
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23)	<	7	=2		3)3		3	G#-#	22#	-2		3	3)	
: ;	 7	 =2	 -1	 .	 1	 )#	 .1	 +	 	 22	 	 .	 "#3	 -#	 .1	
--##22*	1C<	#3		7&		3	#))	3	3	67	2341	21				
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2.2.5 Rationale for combining anti-PD-1 effects with radiation 
		4	4	)	3	3	3N	--#	1-		3	""	"	)				
#	 *	 3	 3	 )1	 "	 3	 --#	 1-	 -	 3	 	 G#	 	 	
=2-	#-#		-	3		1		43	#	32#	""1	4			-	3	
C		G#			2	:';		
04*			1	1	3	3		)1	--#1	3			=2	3		2	
"	3	--#)	""	"	)		:;	:&;		#		3		)	#-#		
)	"			2			)	--#)		3	232	-	""*1	3	
3-321	 3	 	 2	 G#	 	 3	 2	 #%	 	 #"	 	 "	 #<	 3	
=#		"	3)3-.1	)#2	2	>	:0@>;		3	#	2<			
"	 	 2323	 :+;	 #-#	 	 3	 *	 	 #)	 2312	 3)	 3	
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	2*	-	"	3	--#	1-<	43	3	2		*	3						#	
*	3		#-#2"				#	3*	-	3		*	#-#	12	
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"	#-#			""<	43	3	#	-	#2	)#	"	0
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&	321<		
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)		"	((	
 
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	3)1				"#		321	3	21		#1	*	3)3	.)	
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	"		#-#	#	43	--		""			3	9F<	>		*1	.)	*2	43	
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"	3	4	3)1		*	#)		-.	2*		22*	3	#	
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3			43	"		#22)	3	"1	"			"	  	@1		 	"	*		4C	"	223	
3				43	3	3	4	:'<	' ;	2	3	.)		#	#	"	>		3	
-)-	"			
	
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"-	-	)#2	#)))	3	-.	-1	-	43	>	-1	.	-	""#	3	4	
	321			-#	32			)-	-<		#)1	:;	43		@1	
4			-.	43		.	+	.			)	-	#			#.	
"	-<	433	4			43	3	-	-1		:'';		-	1	"	.	#	
34		1=			3	-.	-1	-			)#1		04*	
3		.4			--#	""		"	-	-2=	.#))		-	3	
-2=		.1	)	>'+	-#	--	4		#2		 	@1<	)*		*#	
"	/	:'&;	5	)	"<	#-#			#-.	"	#-#2"		4		
	2	04*<		3	3)3	<	3	4					)#1	<	433			
4	)#	3	--#	2	5			& 	@16"	-		2#	3	.	
#-#			#-#	2"		2	43		-)	4	)#1		#-.	+	
"#3	#1	#22	")		-		,#	43	--#321<	.1	)	

7+	.	43				-#	.		-		4		43		@1	U	<	!	@1	U	
<	 	 '	 @1	 U	  	 "	 	 -.	 43	 -	 .1	 )	 
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"	 .#	 	 )	 321	 #	 	 .2	 ""	 43	 #	 43	 
7+	
.1	:'!;	04*<	3	2	#1	-2)	.*			)	"	
		3	.*	<	#3			)		"	8 	@1<	-1				*1	
	#-#		?3	 	@1	U		"	)*	*		4C	4	-2	)		)		@1	<	
	--#	2		#-#	#	22		.	.)	.1	3	"	
	V!W	3	2				2"1			-	34*	=2		.	-	
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		3	-	)	"			+		
*	3	32	.4	321	<	"	/		--#	21			-2=			

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1-	
	
2.2.6 Pembrolizumab Clinical Trial Data 
2.2.6.1 Pembrolizumab  
-./#-.			2		3)31	*	3#-/	-	.1	:-+.;	"	3	)@6C22	
12	)		1	.C	3		.4				)<	7		7			
	
2.2.6.2 Clinical Trial Data  
FA$!			23	.		<	*#)	2-./#-.			2	-			*1	"	
*		#-#	3	#1	4	3	"	7	2*1<	"		--.#	=2		
JM	"	#-#	<		7	2*	.		-<	#)	3	7	.1	
		:C;	
	--#33-1	"	3	!	2	43			"	7	=2<	!	2	: M;	
4	7	2*	 	2	4			3	#1<	43		-	)	"	' 	1<	2-1	
-	:'!M;<	43				2		"	-	:!!M;	3	-	--	3)1	4	23	
:'M;<	"4	.1	-	:!M;		.23	:!M;	:'(;			
 
-./#-.	4				-)6C)	*#1	*1		4C	"	3	 	2	43	<	3		
		4	&'M	:( M
%	  	8	(;		&	2	43	2	2			2	43	.	<	
		.1	
		3	-	#	-	4		4C	:)%		8	S	4C;		3	
-	#-.		"	-	4		:)%		8	S;	:'(;	3	-2	43		2		"	KM	
	43		-	:&;	3	-	4	4			3	3<	43	1	)	--	
*	*	.)	")#	:M;<	#	:M;<	3)	:'M;<	2##	:M;<		1	-#3	:M;	
@	J	*	*	#		+7			2	:M;		3-.12		3	2	:M;	
3	4		-	3		#	#		-	*	*	:'(;	
@*	3	#<	2-./#-.		.)	#	"#3		<	#	"	7	=2<		3	
	)		3	=	"		23				:$
((&;	:&;			
 
2.3 
Rationale for the Trial  
	
3	.2	""	"				23-	"	#-#	)					"-	3	2-1		
"	321	:&';	7	321	3	.	34		#	.2	""		*	12	"	
<	#)	--<	1-23-<		-		$
7
	:&&!;	3	""		.#		
*	"	3	1-	--#	2	#	"--		C4			)	
2<	 #.G#	 #-#	 )<	 	 	 #-1<	 3	 3	 #-#	 --#	

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)		"	((	
 
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	"	3#	:!;		1<	3	.2	""	3	.	.		3	=	"	2	
*)	--#321	#1	43	321	5	=-2<	5-			.			"	
.2	2			2	43	*	$
7
	43	*	2*	32	321	43		
2-#-.	3	2	4		 	-3	"4)	321	:!;	=2-		"-	-#2	
	-	3*	2*	#""	*		22		2)-	3"<	43.1	-	"	3	""	"	
		)/		.#)		1-	#-	--#1	3"<	3		2*		"	
321	 	 -	 	 	 **)	 	 3	 "	 	 24"#	 ,#*	 "	 --#321	 3	
-.	)1			3	#				""	22#		3	3	--#	
1-		=	#**<	*	-)	-		3*1	2		2	:&;	
-.	
	"	--#321		>		G#		=2	3	2	"		3)	3	""	"	
--#321<	.3	1		.21<	43	3	-	"	-2*)	#-	"	2	43			3	
	2				3	.1		"1	"	--#321	43	>			3			
2	4	C		3	"1		.1	"	2-./#-.<			-	.1<	)*		
-.	43	>				2	43	#.				=2	3	>	"		H	)-	
			*	"	@1	4	.	#)3		-#	3	--#	1-	
	
	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
3 
STUDY OBJECTIVES & ENDPOINTS 
3.1 
Study Objectives & Hypothesis 
3.1.1 Primary Objective & Hypothesis 
• 
.,*%			3	"1		.1	"	>			43	2-./#-.		
• 
0123%	>				.	"1	-		-.	43	2-./#-.	43#	
)"		-)	#	=1 
3.1.2 Secondary Objectives  
• 
	.	3	"1	2"	"	>				-.	43	2-./#-.	
• 
			."	43	*	2		:;<				:
;		#	
"	2	:;	
• 
		2			23	*#	-	3)	#.12	"		
• 
		2					#-#	67	=2	
• 
		2)	"	#**	:5;		*	#**	:; 
3.1.3 Exploratory Objectives  
• 
	"1	.-C	3		43	--#)	2		321	
• 
	1	223	.	-2	"	$+	
3.2 
Study Endpoints 
3.2.1 Primary Endpoint 
• 
		3		-)	=1	:7;	"	>						*	"		@1	)*			
"	43	-.	43	2-./#-.	
3.2.2 Secondary Endpoints 
• 
		#	=1		:"		#2			4C	"		>	";	#)	

	+	* 	
• 
			=1		:"		"-		4C	"		>	"			#	!	1	
"	3			"	2-./#-.;	#)	

+	*	 	
• 
	#	3	<	
			#)	-
				
• 
	#	3			
		23	*#	-	3)	#.12	#)	
-
				
• 
		3	"G#1	"	67	=2	.#		2		2	
• 
	-#	3	5				'			-3	 
3.2.3 Exploratory Endpoints 
• 
	3	#-#	")	1-231		#-#	)		3	#-#	.2	3	
--#33-1	1	4	#<	.#		1	.	-	<	3	"4)	
-C%	
<	
!<	5I2<	<	7<		7	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
• 
		"	*	"	$+	2		2	>		
4 
STUDY DESIGN 
4.1 
Summary of Study Design 
3			-	2.	23			"	2-./#-.	)*		-.	43	>		2	
"		2#.			2	43	#.			3	#1	4	#	#2		!	2	43	
	3	2)	.1	"	"	2*	3-321<	43		2#-.	#.<		4	
G#	"#3	2*	1-	-<		3*		"	2*	3-321<	34*	
-#	3*	.		#.	"		2#-	#.	3-321		
	
4.2 
Treatment Regimen 
3	#1	4	.	#		4	2R			"1	23	:	+;<	"4	.1		=2	3	
:	>;	3		"1	23	:	+;		.			S	)	#3	3	2	4	.				3	
"	'	2	+	-=-#-	"	'	2	4	.				+	=2)	>		@1			"		
-.	43	2-./#-.	"	3		-	3		7		3	"		2		4		-	7	
	3	"	'	2<	3	-	-.	4	.	-		.)	#2.			4#			
-	"	3	#1	#)	3	=2	3	:	>;<		2	4	3*	>		@1			"	
43	 2-./#-.	 	 .	 	 "1	 	 2	 	 	 2-./#-.	 4	
#	#		2)<	#2.	=<	3	2	434			3	<		3	
2	3	-2	 	1	"	-	+	-=-#-	"	!	2	4	.			3	#1	
	
+	2	4	*	2-./#-.		1	:
;		1	:;	<			+		>	"	3	#1		+	2	4	
*	>		
 <	
&		
(<		2	>	2	:	+22=	;			2	+	4	
*	>		@1		H				>	4	*		@1			"	"		"	"	2	+	
+	2			+			>	4	*	2-./#-.				-)	*1		4C<	#		
2)<	#2.	=<	3	2	434		"-	3			3	2	3	-2	
 	1	"	-	
	
	3		"1	3<		--#-	"		2	4	.			3	>		"	@1			"	
-.	43	2-./#-.	3	)2	"	.4	3	-	"	3	#.G#	2	4		"	
3	 	 1	 "	 -./#-.	 	 3	 2*#	 	 2	 	 -)	 )	 -#2	 2	
#"")	"-	#	=1	3	7	2	"	3	#1			4C	"-	3			"	>	:		

';		#			+	4	.		.1	3	"1	*4	
--	:
;		3			
'3	2		3		+	3	3	-2	3	7	2	"		#	"		2	=2		7<		"		
#	"		2	=2		7			+<	3	3	3	4	.	=2		'	2	"			'	2	
=2		7<	3		4	.	2.		-*	"4		3	=2	3	:	>;	04*<	"	J	
		'	2	:	-	3			3	"		2; =2		7	3	3	-=-#-	-		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
:+;	4	3*	.	3	"	3	+						*	"		@1		H	3	3	#1	4	.	
-	 
?3	4)	"			'	2		-2	3	7	2<			2	4	.	#	5#3	
2		1	.	#	"	3	
	3	*4	3	=1		"	3	3		2			>	
	.)	-2	2		3*)	-2	 	1	"	2-./#-.		-#	#		
-1	--	"		&	1	#2	#.G#	<	3	
6	4			#	43	3	
2		<				.1		.	"	3	#	"	2-./#-.			
	
6	>		*		2-./#-.	)	#)	3		"1	3			=2	23		
!& 
7!
(

$
	"1 3
	-)	*	*		-#<	*1	
	4C
 @1		H	:1<	?1<	51;
=2	3	
	-)	*	*		-#<	*1	
	4C
	@1		H	:1<	?1<	51;	
>%		+.*	>1	321R	@1%	@1R	*%	*#R	-)%	-)-R	H%	"	
	
4.2.1 Dose Limiting Toxicities  
+#	=1	4	.		#2			#)		-3	"4)	3	"	"	"	321	:	
	
';		3	
	12		:+22=	;	4	.	#			12		.6	-	
	3	
--	=1	
	"	+*	*	:

+;	*	 	4	.	#		)		#)		
>	.*	=	:+22=	;	3	
	4		=2	"	3	'3	2		3		
"1	3	3	-2	3	7	2		*4	3	=	."	#-		3	=2	
3		>	
 
+1	7	-#	.		=1	3			2..1<	2.1		"1			3	-.	"	
2-./#-.		>		7		"		"4%	
Haematologic: 
• 
$#2	43	"*	)					#2	)		
• 
3-.12	43	.)	)				3-.12	)		
Non-Haematologic: 
+1	J		3-)	=1	433		"1<	2..1		2.1			3	-.	"	
2-./#-.		>	"	2#	-3-	#)	3	"4)%	
• 
	
	12		L		)	"-	.	6	#	12	)	J		:	


+	12	)	J	;	2)	"	L	&	1	:#)	4C;	
• 
#-	)	J		2)	"	L	&	1	:#)	4C;	
• 
23)	)	J		2)	"	L	&	1	:#)	4C;	
• 
=1	)		#2	"	321	"	L	&	1	:#)	4C;	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
	
)	"	3	#1	4		2	#	3	"4)			"	.1	3	
%	
• 
"		#	"		2	=2		7<		"		#		2	=2		7<		"#3		2	
4	.	#		3		*		3		"1	3	
o "	 	 #	 "	 '	 2	 =2	 	 7<	 	 "	 	 #	 "	 '	 2	 =2	 	 7<	 3	
2)			>	"	3	#1		2			
o "	J		#	"	'	2	:	-	3			3	"		2;	=2		7<	3	3	4	
.			>	=2	23		3	#1	4	.	-		
	
4.3 
Study Schema 
 
F6	3-	)-	"	#1	*		4	*	2-./#-.				-)	*	*1	
	4C	:		.1	;	>	"	2#	-3-	4	.	-		1		1	 <	&		
(	:		.1	;		
 
4.4 
Follow-Up after stopping Pembrolizumab 
4.4.1 30 Day Safety Follow-Up Visit 
+	2	4	.	G#				"1	"4#2	*		1	"	3			"	2-./#-.		
."	3		"		4		-<	433*	-	"		43		-		
	2)<		-2	3	-	2	4					"1	"4#2	*			
.*	+	*	*	:+;		#	*	*	:+;	3	#	2		3	"1	"4#2	*	
3#	.	2		.			!		+"	3	"1	"4#2	1	#*	+		3	2N	
	*	3#	.	"4	#2	"		)		-1	<	.#	43#	"#3	)		3	
5		
	
4.4.2 Follow-Up for Discontinued Pembrolizumab without Disease Progression 
	43	#	2-./#-.	"	1		3	3		2)	4	-*		3	
"4#2	23		3#	.		*1	(	4C	:'	X	&	1;		.1	)	-))		2		
"			-		#	*1	""	3#	.	-			"-	))		#	
1
3
2
4
5
6
7
8
9
11
13
12
10
Time (Weeks) 
Dose limiting toxicity period
Stereotactic Body Radiotherapy
MESO-PRIME Treatment Schema
Pembrolizumab 200 mg i.v. every 3 weeks 
15
16
14

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
#	 3	 	 "	 4	 	 321<	 	 2)<	 3<	 434	 	 	 "	 3	 #1		
"-	))	2#1		-	4	.		"	4	-			
	
4.4.3 Survival Status Follow-Up Phase 
		2	=2	"-		2)				4		321<	3	2	
-*		3	#**	"4#2	23		4	.	"4	#2	*1		4C		-	3		
#	3	4	.		.1	*4)	3	-		6	)	3	2		@	1		
4	-		3	"4#2	#	3<	434	"	<		3		"	3	#1<	433*	#	
"	
	
4.5 
Study Termination 
3	Y"N		"		3		43	3		2	3	-2	3	Y""#1N	*		3	"	
"4#2	*<	433*		322			
4.5.1 Clinical Criteria for Early Trial Termination 
1		-	4	.	3	#	"	3		2"	.4%	
 D#1		G#1	"		)		#		-2	
 	3		2		)#1	G#-	
 		*1	"	*	#)			3		3	#			2	33	
3/		2	
 		-"1		#	3	*2-	"	3	#1	#)	
  "	7					+			#	"				#	"	'	2	
		43	3		"	#221	)-	43	<	-2	"	4	.	2*		3	
2	 :*	 
9;	 	 	 3#	 	 	 3	 #)	 #221	 3)	 3	 	 	 4	 -	 "	
222	,#-		.	-		)		3	2N	-	
	
4.6 
Treatment after End of Study  
54)	22		3	#1	2		4	.		.1	3			)			
2	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	(	"	((	
 
5 
SELECTION OF PATIENTS 
5.1 
Screening and Enrolment 
3	*)		3	#1		4	C2			"		2		"	1		3	#1	
2	"	
3	)	)	4	.	"		3		5	5	3	2	3	2-1		"	=#	4	.	
	)		.		2	"	3	2N			4	.	#		-	).1	
2*	31	"	43	3	2	"	-	?	"-		-#	.	.	2		
3	2	#))	1	#1	2"	2#	
	
5.2 
Registration 
?3	3	2	)	3		"-	31	4	.					3	4	.	#		"1	3	2	
"		"##	-		
		.	)						#-.	.1	)	3	
9	%	
23%		!'	' 	
5=%		!( 	'&'	
-%	-.Trial@rmh.nhs.uk	
>4	1		51<	(	-			2-	
	
		3	)	-	3*	.	-2		3				3	
5	3	2	4	.	
	"	).1	"	).<	3	2	4	.)		3		"	3	2			).	3	3		
*)	4	-C	*	)-	"	3	-	"	3	2	3			4	.		#G#	
#-.	3		)	4	.-	3	2-	#1	"	"	3	2		3	*		2	
	)		3	#1	.#			.)	-<	3	3	2N			4		.	)	
-	 4	 .)	 43	 &	 1	 "-	 3	 	 ).1	 3	 .	 "-	 	 	 #	 2	
"1	2	4	1	.	"		
5<	3		2"	"-			--#		

9	#)	3	)					3	*)	2.1		-		"		
"	3	1		"#	-<		"	.3		32	#-.	"	3	2			3	#1		3	
)			+	3		"	3	#1	3		3#	.	3*	)	43	3		5	
	
5.3 
Patient Replacement Strategy 
+	2	-1	.				)*	3		#	3	3	G#	#-.	"	*#.	2	
	3	3		3*	+	2	3	#	3		"	2)*		43		-3	"	3	
		"	321	4		.	*#.	"	7		3"	4			.	2	+	2	3	
#	3		"		#)	+	4		.	2		4	.	#		3	*#.	22#	
"	 2	 "	 3	 2*	 3	 04*<	 2	 "#	 	 3*	 *	 2#-	 	 
	 "	
2-./#-.		1		"	321	4	.	-*	"-	3				.	2	+	2	43	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
		3	"4#2		-3	2	-2	"	>	"		"		3	3	2)		
=1		.	2	.1	4	2		3	3		#	3			--#-			:	'	"	G#;	
2		3	3	

5.4 
Entry Criteria 
3	"4)	).1		4	)			2	"	43-	3	2	-			
222	 +	 *	 -	 	 -	 	 3#	 .	 C	 	 	 43	
)	433	3	2		#.	"		2#	2	).1		-1		.	4*	.1	3	
*)		
5.4.1 Inclusion criteria  
			.	).	"	22		3	<	3	2	-#%	
 	3#	.	J!	1			3	1	"	))	3	"-		
 	-#	3*		3)		1)	)	"			
 	3#	3*	1	.		:		.)		"	=2#	
2#--1		2#-1		;		
 	-#	3*	-#.				.1	-
	:					-		"				
			""	*;		
  	-#	3*	3		2)		.		"		"	2*	
3-321	"			43	3*		"	2*	3-321	-#	3*	
.	#.	"	2#-#.	-.	3-321		
' 	3#	3*		
@	2"-	#		
& 	3#	.	.				#	"		321			.1	3	
*)	
! 	3#	3*	2#	.	<	41	"-		##<		#.	"	-	
	2	"		43	>	"	2#	-3-	
( 	-#	3*	G#	)	"#	#)	
	12		K		G#	
.	#)	"#	<	43		5	L	!7		LM	"	2			7
	L	M	
 -	G#	)	"#				.		:.		.	43		1	"	
;	
 0*	2*	#	"-		3*	#	-2		41	.	#	-2	
 	
13. 5-	2	"	3.)	2	3#	3*		)*	#-	2)1	43	&	3#	2	
	*)	3	"		"	#1	-	:
;		5-	2	"	3.)	2	3#	
.	4)		#	3)31	""*	-3	"	2	"	3	#	"	3	#1	3#)3		1	
"	3			"	#1	-		5-	"	3.)	2		"		4-	"4)	
-3		#	.-)	2-2#	#	2-1		-		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
-3	
#	
31-1<	
.	
2)-1	
	
.	
23-1	
+	
2-2#			"			-	"		-3	43#		*	-	#	 
 	2	3#	)		#		G#	-3	"	2	)	43	3	"		"	
#1	321	3#)3		1	"	3			"	#1	321		
  >	4)		2*	"-		"	3		
 
 
Table 2: Adequate Organ Function Laboratory Values 


&
3
'

• 
+.#	#23	#	:+$
;	
J 	=	(67
• 

	=	(67
• 
0-).
J(	)67 	J '	--67	

• 
#-	


• 
#		#		

	
Z 	I	#22	-	"	-	:97$;		
	

J'	 -76-	 "	 2	 43	 	 *	 L	  	 I	
#	97$	

		3#	.	#	2	#	
'

• 
#-		.#.						
• 
	.#.
Z	 	I	97$	
Z	97$	"	2	43		.#.	*	L	 	97$	
• 
+	:@;		+7	:@;
	
Z		I	97$		
8 	I	97$	"	2	43	*	-	


3-.	-	:;
	
Z 	I	97$	#	2		*)	)#	321
	)						43	32#	)	"		
#	"	)#
+*	 	 3-.2	 -	
:;	
Z 	I	97$	#	2		*)	)#	321
	)						43	32#	)	"		
#	"	)#
	
5.4.2 Exclusion Criteria  
3	"4)	2	-#	.	=#	"-	22)		3	%	
 	43	3*	C	1	*)	-	2#		3*	#		*)	*	
43		4C	"	3	"		"	2-./#-.			4		22			
.*	#		
 	43	3*	*	2	3-321<	)	-	-#	321		321	
43		4C	2		3	"		"	2-./#-.	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
 	43		)	"	--#"1		.	*)	1-		321	:L& 	-)	"	
2	6	L	-)	"	=-3		3	G#*	;		1	3	"-	"	
--##22*	321	43	&	1	2		3	"		
 	43	*	"	*	#--#		G#)	1-	-	43	3	2		
-3			#-	31	"	1	*	#--#	<			1-	3	
G#	1-			--##22*	)			#--#		3		#1	
G#	""	1	-<	.#	-		C	"		)"	"	"			3	2		
  	43	3*	*	2	321	43		<	7<	7<	
&<		

1=	1-231	)	:
7+;	.1	:#)	2-#-.		1	
3	.1		#)	2"1	))		-#		3C2	2341;	
' 	43	*	"	*		*#	1-	:
$;	-	6	-#	
-)			43	2*#1		.	-	-1	22	2*	3	.	
-		.		3			*	"	4		))	.	-		
& 	43	3*	3	2*#	321		3	3=		3	)3.#)	)	3	4#	
2#	3	"	-	"	>	"		
! 	43	*	"		#)			*<	"#	2#-	
( 	43	*	"		-)1	3		2))		G#	*	-	
 	43		31		#	*	"	1	<	321<		.1	.-1	3	
-)3	"#		#<	"	43	3	2N	22					3	.		"	
3	2		
 	43	213		#.	.#		3	4#	"	43	2	22
 	43		2)	6	.")		=2)		*	43	3	#	"	3	<	
)	43	3	)	*	3#)3		1	"	3			
 	43		31	"	0<	0	6	.<	02	>		02	
	
 	43	1	*	"	G#)	1-	-	
15. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment. 
' 	43	C4	312*1		3	*	#.	2-./#-.			1	"	3	
=2			3	>	
  	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
6 
STUDY PLAN AND PROCEDURES 
6.1 
Study Schedule 
5-	 #1	 1<	 2	 4	 .	 	 *1	 	 1<	 2	 	 3	 -	 "	 3	 	 "	
2-./#-.	#)	4C		"	>	"	<	2	4	3*				*4		
4	 #	 	 .	 	 	 1	 	 2-./#-.	 #	 31	 3*	 	 2)<	 #""	
#2.	=<	434<	3	#1			3*	-2	 	1	"	2-./#-.	-	
.1	2)		 	1			.	#	43	3	#1	2				4	.	
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2	3#	.	"-			-1	-	"	4	"-	.-	*.	3	-1	.	*		
3	2N	4)		#	22		3			3	--#	"	3	"-	4	.	
2*		#-	*		*		"-		#-		3	)		"-	3	2#	
3	2N		)#	3	"-		4	3		
	G#-<	22.	4		
)#	
	
6.2.2 Inclusion/Exclusion Criteria 
+	#		=#		4	.	*4	.1	3	*)		G#"	)		#	3	
3	2	G#"	"	3			

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
	
6.2.3 Demographic Data, Medical History and Treatment History 
-)23			4	#		"	.3		631	+	-	31	4	.	.	
.1	3	*)		G#"	)			31	4	#		*	<		1		
)	43	3	2		1	3				.	1	)"	.1	3	*)			
))	3		"	433	3	2	3			3	#1	4	.		21				
	-	31					3	-	31	3	*)		G#"	)	4	.		
3	2N	#		#		-	31	#)	2		#		))		
#<					2		-	#)	1-	-<			#)	
	
6.2.4 Subsequent Anti-Cancer Therapy Status 
	3	#	"-	2-./#-.	"	1	3		3		2)	4	3*		
"4#2	*	*1	(	4C		433	3	*)	3#	*4		4		321		
"	3			"	2-./#-.		"		2			4		321	43		1	"	3	
		"		-<	3		1	"1	54#2	*	-#	#	."	3	"		"	3	4	
321			4		321	3	.		3	2	4	-*		#**	"4#2	
	
6.2.5 Survival Status 
3	*)		G#"	)	4		3	2	"	#**	#	3	-	4	#	
3	2	#		"	22.		"	2	3			"	2	3	.			"4#2	
#**	"4	#2		.		*	3	23		
	
6.2.6 Prior and Concomitant Medications Review 
6.2.6.1  Prior Medications 
3	 *)	 	 G#"	 )	 4	 *4	 2	 -	 #<	 #)	 1	 22"	
43#	G#-<			2	-	C	.1	3	2	43	!	1	."	)	3	
		-	"	3		"	433	3	2	3			3	#1	4	.		21	
					2	-		
	
6.2.6.2  Concomitant Medications 
		3	*)		G#"	)	4			-<	"	1<	C	.1	3	2	#)	
3			+	-			2.	+		*		*	=1	*	"			
:
;	3#	.			"			!	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
6.3 
Clinical Procedures/Assessments 
6.3.1 PD-L1 Assessment 
	22		3		2		*.	#	"		#-#			2*#1		:#-#	
2))			2		"			4;	"	7	3	3	2-	4	.	*#	
			.1	"	=2	#	"	7	.1	3	7	0
	
	23-=	:C;	"		#		
*.<	3	"4)	"-		31	3#	#)		.21	"		#-#		"	.-C	
1	$%		22)		3		4	.	#	"	3	7	#		
	
	
6.3.2 Adverse Event (AE) Monitoring 
3	*)		G#"	)	4		3	2	"	2	4		4)	+		2"	
	3	3#	"	#1	-	:.	;		-	"G#1	"	1			+	4	.	)	
		"-	"-	"	1		3		#	3	2		1	"1	"4	#2	*	)	
	

+	* 	:	+22=	;		=	4	.	3		-	))	#<	#1<	
=1	))<			C	43	)			-		
	
+	+	"	#C4	)1		43	2-./#-.	=2#	3#	.	*#		-	"		
	2.1		*	"			:
;			21		--#		*	*	:+;			
+22=	 	))	3	"<	*#		-)-	"	+	"		2	--#)	
)1			"			!	"		"-	))	3	-		)	"	+			
	
6.3.3 MRC dyspnoea Score 
3	 *)	 	 G#"	 )	 4	 	 3	2N	 12	 #)	 3	 
	 12	 	
:+22=	;		)	2		3	-	2	"		3	#1	3#	"	-	:.	;			
	
6.3.4 Full Physical Exam 
3	*)		G#"	)	4	2"-		-2	231	=-		)	2		3	-	
2	"		3	#1	3#	"	-	:.	;		
1	)"	.-	")	3#	
.			+	#)	3				
	
6.3.5 Directed Physical Exam 
5	1	3			G#		"#	231	=-		.		3	3#	"	-	:.	;<	3	
*)		G#"	)	4	2"-			231	=-		1		2			
-	-			
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	(	"	((	
 
6.3.6 Vital Signs 
3	*)		G#"	)	4	C	*	)		)<	2		3	-	"	3	
	"		-			-	#		2"		3	3#	"	#1	-	
:.	;			)	3#	#	-2#<	2#<	21	<	=1)	#<	4)3		.	
2#		0)3	4	.	-#		)	1	
	
6.3.7 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
3	 *)	 	 G#"	 )	 4	 	 
@	 #	 :+22=	 ;	 	 )<	 2	 	 3	
-	"	3		"		-		#	"		-		2"		3	#1	
3#	"	-	:.	;			
	
6.3.8 Pulmonary Function Tests 
5#	#)	"#		-	4	.	2"-		)<	2		3	)	"	2-./#-.		
2"		3	#1	3#	"	-	:.	;		
	
6.3.9 Pregnancy Tests 
5-	2	"	3.)	2	3#	3*		)*		#-	2)1	43	&	3#	2		
*)	 3	 "	 	 "	 #1	 -	 	 2"	 	 3	 #1	 3#	 "	 -	 :.	
;+	 #1	 2)1	 	 4#	 .	 2"-	 	 3	 2	 	 3	 	 "	 3	 1	 "	
-./#-.	#)	3	-	2			3	"1	54#2	*			
	
6.3.10 Haematology, Biochemistry and Urinalysis (including, -hCG†, PT, aPTT, fT3, fT4 and TSH) 
+	.1		4	.	2"-		)		3		-		*1	*		"		3	
3#	"	#1	-	:.	;	-2	4	.	1	.1	3		#1		.1	#)	
	-3	"	#		7.1		"	)		.	2"-	43		1	2		
3	"		"	-		+"	3		2	.1	2#	3#	.	#		-	3	
&	3#	2		)		#	-#	.	*4	.1	3	*)	6	)		"#		.	2.	
2		3		"		-	3	*.			.		4	.	-#	
	
 


	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
Table 4: Required Laboratory Assessments 
'

%

:

%
0-
+.#-
>
	
0-).
+C	2323
@#

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323
	
	
	
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#-	2)1		4	.	G#			
	
	
6.3.11 Tumour Imaging and Assessment of Disease 
6.3.11.1 Baseline tumour imaging 
-))	3#	.	#C		"-	3	3	2	3			3	3=<	43	>	"	2#	
-3-			222		3			-#.	#)	-
	3		4		.	
	"	=3			
	
6.3.11.2 Timing of Disease Assessment 
#-#	-))	4	.	2"-	.1	
	3		#-#	-))	4	.	2"-		-	3	!	
1	2		"-	"	).1		2"-		2	"	#		-)-		
2.	"	#		3	)		"	31		"	)	G#1		2"-	43	3		
-	44		
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
#1	-))	4	.	2"-		)	*1		1	:*1	(	4C;	"	3	"	'	-3	:X	&	
1;	3	*1		4C	"	'	-3	:X	&	1;<		3#	"4		1		3#		.	
,#	"	1		1			=	"	2-./#-.	1	"G#		#-#	-))		
-	 2	 	 	 "	 	 3#	 .	 2"-	 "	 2	 -)-	 	 -1	 #	
	-))	:)	.	;		-))	3#	#		.	2"-	#	#-		
2)<	3		"	4		-<	434	"	<	3<		3		"	3	#1<	
433*	#	"		
	
6.3.11.3 Confirmation of Disease Response  
	-"	
	:+22=	';<	2	3#	.	"-	.1		2	)23	-		
	3			'	4C	"-	3		3	2	4	"	#-	3		"	"-	"	2	
-1	.	2"-		3				'	4C	"	3	"		"	2<			3	=	3#	
<	433*		1		
	
--#32#	 )	 -1	 2#	 #-#	 ""	 .1	 2)	 )#	 2"	
--#	2	3	2	2		43	#3		223	-1	=	.1	3	12	-	
#	"	2		43	1=	)			-"			2	"					
#-#	.#	 	 *	3	 22	 "	 4	 	 3"<	 -"	
	 -1	 	 2*	 	
#	2	-	"	--#32#	)	#3		2-./#-.	
	
3"<	-"	
	4	.	#	43	3	"4)	2%	
• 
"	)	-))	34		2)*		:;<	#-#	-	3#	.	2	
'	4C					"-		43	3	2	"	#)	-	43	4)	)	
"-	"	2)		
o 	-1	#	-	43	4)	"	"-	"		"	31		1	
.		"	.1	3	"4)	%	
 
+.	"	)		1-2-	)		2)	
 
$			
@	2"-	#	
 
+.	"	2	2)	"		
 
+.	"	2)*	#-#			-		G#)	#)	*	
-	 *	 ?3	 ".<	 2	 3#	 	 .	 #	 #	
2)	 	 "-	 3	 4	 	 #	 -	 2	 	
)	2)	C		#	3	.*	3	-	2		3*	
		#-#	"		3	"	"4	-3	"	3		"	--#321<	.#	
43	#.G#		2		3		-	1	#.			
G#		3*	2	-))	"	"-	"	2)*		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
• 
"	2	-))	34		#		3	#-#	.#	-2		3			-)	
<	-	-1	.	#	6#-		
• 
"	2	-))	"-	2)*	<	2	4	.	#	"-	#1	321		
o $%	"		2	43	"-	)23	2)	:					!	1	
2	-)	2)*	;		1	.		1	-2*<		3	
		"#3			3	#-#	-		3	"-1	<		=2	-1	
.			#	-	#2	#	43	3	2	:*	
9;		

1	.	2	3#		3*		3	"-1			"#3			3	
)	<		#G#*			)	<				4		
*2	:4)	;		#	#1	-	
	-)	433			3	#-#	.#	3			<	*)	3#		
	)			4		)			
	
6.3.11.4 Confirmation of Disease Progression 
	2)	3#	.	"-			3		4C	"	3	"		)	2)*	
		1	.	2		43	3*	#"-		2)	-1	#		
-	#	2)		"-	

1	.		"	.1			-	"	3	"4)	%	
• 
+.	"	)		1-2-	)		2)	
• 
$			
@	2"-	#	
• 
+.	"	2	2)	"		
• 
+.	"	2)*	#-#			-		:)<		-2;	G#)	#)	
*	-	*	
	
6.3.12 Tumour Tissue Collection and Correlative Studies Blood Sampling 
6.3.12.1 Archival Tumour tissue samples 
5	2	43		)	.21			".<	3*	#-#	-	-#	.	2*	"	3*	
.21	:.C		;				-#		#-#	#	"		.C		*.<			-	"31	
22	:)	43	3		'	-3;	#	 	-		3#	.	2*	+3*	
#-#	.C	4	.	#		#		3		"	3	#1	<	#2	G#<		"	G#	"	3	
2N		-)-	
#		4	.		.1	3	#1	-	3		3*	-2	
		#3	22)	2	4					=	*		#)	=	2#	+		
3*	-2	4	.			2-	-2		#		#3		3	--#)	*#	
	.	.4	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
6.3.13 Tumour Biopsies and Research Blood Samples 
5	2	43#	3*	-2<	#-#	.2	4	.	.	#)	3	)	2	"	3	
2		2	3	.	-2	4	.	.		
<	
<	
 			3		"	#1	
*	 :.	 ;	 #-#	 	 .	 -2	 "-	 3	 #1	 -1	 #)	 2-<	 )-	 	
2	1	+	3	-1	*#	"	-2	"	2)	2*		
		2-./#-.	321		321	+1	-1	#<	.#			-	%	
• 
%

$	&


--#33-1	:0
;	4	.	#			3	#-.		-2	"	--#	"	
			"	3	--#		#.	2	43	"-"=<	2""	-.	:55;	
#-#	 #	 ."	 	 "	 =2#	 	 321	 3	 0
	 1	 4	 #<	 .#	 	
1	.	-	<	3	"4)%	
<	
!<	5I2<	<	7<		7	
• 

!"<
3	.	-2	4	.	1	"	$+		

	+1	"	

	4	#<	.#		
1	-		3	"4)<	3	)	2"-	"	7	)	4	.			


	-2	43	0
<		43	2			2)		
	
6.3.14 Chain of Custody of Biological Samples 
		<	2	4	.		"	3			#	"	3	.)	-2			"#	3	"	
#1	 4	 .	 -	 "	 	 -2	 3#)3#	 3	 "1	 3	 *)	 	 2.	 "	
-)			"	"#	.1	"	.)	-2		"-	2	43	3			)	
	3	<	3	#	32-		2	+1	43	#1	"	3	-2	)	#.	*	
2*	 4	 3*	 	 C2	 "#	 .1	 "	 -2	 "-	 2	 	 "#3	 32-	 	 2	 :	
222;	 
9	4	 C2	*	 *)3	 "	 3		 "1	 3#)3	 	 2#	 	
-)	"	#1			
6.4 
Total Blood Volume 
3		*#-	"	.	3	4	.	4	"-	3		2	"	3	-	.		3	
	.*		34		.	 	 
Table 5:  Volume of blood  

 -.
$

 
-.
#	0-)1
'

''
#	
3-1
!

!!
#	%
 
3	>	-2	
$+7
'	
	
	
#1	%
(
-"%#% # ". 	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)		"	((	
 
7 
TREATMENTS 
7.1 
SBRT for pleural mesothelioma 
7.1.1      Planning and Delivery 
321	2)		*1	3#	.		#			43	3	#		D+	)#	
"		321		*.		G#	"-	0
9		#		+22=		43	
3	2	+	1	2	"				-1	.		3	)	*)	2)	)	4	.	"	3	
"	)	*#-	
7.1.2 Toxicity Assessments  
12			=1	))	43	

+	* 	4	.			4	#	2#-<	#)	
".<	23)<	C	=1<	-1		")#	+	3	+	4	.	#-				
	
7.2 
Pembrolizumab 
7.2.1 Investigational Product 
3	*)		#	:;	"	3	#1		2-./#-.	+	2		3)31*	
3#-/	-+.	"	3	)@6C22	12	)		1	.C	3		.4				
)<	7		7	-./#-.	2	=)	--#	2	1		3	2	"	
)	 	 	 	 2"1	 *	 	 -./#-.	 4	 .	 -#"#	 .1	 	
)		@	#"#)			4	.	2*		3	"-#		.		.	'	
+	"-	.#	3	*)	2#		.	"#		3	*)N	>3#	:>;	
	
Table 6: Product Description 

<

*

-./#-.		-)6	-7
#	"	"#
 
7.2.2 Product Preparation 
	"		3		3-1	#	"	22	"	3	2-./#-.	"	"#		
	
7.2.3 Storage and Handling 
7.2.3.1  Storage  
	"		3		3-1	#	"	.1	"-		#)	.1		)		
	
7.2.3.2 Handling 
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
	"		3		3-1	#	"		3)	#	2"			3	22	"	
3	#)	2#		.	"#		3		23-1	-#		+	3		3	2	*)6)	
)	23-		3	22)			2.	"	#)	3				-#	.		
		#<	-		#	3	)		2"		3	.		2		2)	
"		-	-#	.		.1		#3	2		3				-	-1		.	
#	"	1	2#2	3	3	3			3	2	
	
	3#	"4	3		"	#)	2		*1<	43		2.	""		--	)	"	
3	#	#)	2#	.4	3	23-1		3		
	
	
7.2.4 Packaging and Labelling Information 
-./#-.	4	.	#22	.1			#	"	,	-./#-.	4	.	2C)<	.	
	*		3	22)		"	"	3)	.1		3		4	.	#22	2"1	"	3	
		3#		.	#	"	1	3	2#2	3	3			3	2	3	#)	4	.	.	
			@	#"#)		+=			
	
7.2.5 Returns and Reconciliation 
3	2	*)6)		2.	"	C2)	#	#.1	#		"	
2-./#-.	#)	3	-#	2			#	"	3	2		3	-#	-)	
			3	#	"	3		92	-2		-	"	3	#1<		##	6	21	
#	 	 -	 4	 .	 1	 	 3	 	 2	 #	 21	 	 	 3	 2	
*)N6)	 2.1	 	 )	 "	 2	 "	 	 -21	 <	 2*	 3	
2#	 "	 22	 2	 3*	 .	 .3	 )	 	 22.	 "<	 <	 	 	
#	)#		2#<		2*	3	222		"	2		C2	
	
7.2.6 Doses and Treatment Regimens 
+	2	4	*	2-./#-.	-		2		2#	"4)	-#"#N	
#		-	3#	.)		3	1	"	"-	"	).1					2.		
3			433	-		6)		
Table 7: Pembrolizumab and SBRT for MPM schedules 
! 
&(
!
!
!
*=

$
"


	+	
	@1		H	
-./#-.	
	-)	
	4C1	
	"#	
	>	
	@1		H	
-./#-.	
	-)	
	4C1	
	"#	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
7.2.7 Timing of Dose Administration 
#)	3	#		-	23<	3	2-./#-.	3#	.	-		1		"	3	
1	"		2#6-	3*	.	-2				3	3#	"	#1	-	
:.	;	3	2-./#-.	-	-1	.	-	#2			1	."		"	3	3#	
1		#)	3	#		-	23	#		-*		#)	3	#		
-	23	"	3	<	3	2-./#-.	4	.	-				4C1	1	:.	;		
	
	2-./#-.	4	#	#		2)<	434	"	<		#2.	
=1		.)	-2	2		3*)	-2	 	1	"	2-./#-.	3*	3	
2	"	#)	-<	43		*4		)	-			2)	-	
3#	.	#	43	3	
3"	*)		3	2	#1		-		2#	
3#	.		"	3	.1	7	-./#-.		23	:	.	;							
)	3		"-	"	)	-<	2*	3				3	-	#2	*	"	
3		"-	3	
	5-	
	
+		-	4	.	-			#2	.	-./#-.	4	.	-				
-#		"#	:-	1	*		"#	)3	-1	.		#		=1		.	
		'(;			3#	-C	*1	""		)	"#	-)		.					-#		
2.		04*<	)*	3	*.1	"	"#	2#-2	"-			<		44	"	 	-#		S	
-#		2-	:<	"#	-			-#%	 	-6S	-;	3		3-1	#		
2"	#	"	2-./#-.<	#<	22	"	3	"#	"#<		-	
	<	"#	)3	-1	.		#		=1		.			'	.	(	
	
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3	"#<		-		
	
7.2.8 Blinding/Masking 
3	 	 	 2.	 R	 3"<	 3	 2<	 *)	 	 2	 4	 C4	 3	 -	
-	
	
7.2.9 Dose Selection/Modification 
7.2.9.1 Dose Selection 
-./#-.		.)	)*	#)			-)	"	)	*1	3	4C	3	-./#-.	
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-	"	2-./#-.		2*		3		3-1	#	3	)#		2"	
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7.3 
Concomitant medications 

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7.3.1 Prohibited Concomitant Medications 
		*	2"1	23.		3	=#					4	#)	3	
))			"	3					"		"	3		3	23.	-		*	
3	 3	 2	 -1	 .	 #	 "-	 	 321	 	 3	 *)	 3#	 #	 1	 G#	
))	3	43	3	
3"	*)		)			
	
3	"			1	#22*	321		*		43	3	*)	6	3	2\	
2-1	231		04*<	3			#	3	2			321		*	3#	
G#	3	-##	)-	"	3	
3"	*)<		3	2		
	
		23.	"-	*)	3	"4)	32	#)	3	)		-	3	"	
3	%	
• 
+	1-	3-321		.)	321		
• 
--#321		2"		3	2	
• 
*)	)	3	3	2-./#-.	
• 
7*	*	43		1	2		3	"		"		-<	43	22)		3		
	43	3	"		-3	"	3			"	#1	-		=-2	"	*	*	#<	
.#			-	<	3	"4)%	-<	-#-2<	#.<	3C	2=<	14	"*<	.<	>
@<	
	123	:;	*		"#/	*	"	,		)1	C	*#	*	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
		4R	34*		"#/	*	:)	5#];		*	#	*<	
			4		
• 
@#	"	1	2#2	3	3		-#	1-2-	"-		*	"			"	
#2	--#)	)1		3	#	"	231)		"		-1	.	22*	
"	#	43	3	
3"	*)		)		
• 
321		2"		3	2%	
o $%		#.G#	321	43		-	-		3	3=	4		.	
2-		321			1-2-	1				3	.	-1	.	4	
"	#	43	3	3"	*)<		)					**			1	
2	"	3	#)	
	43		3	-	.1	3	*)<	G#	3	#	"	1	"	3	"-	"	3	
	 -)-	 3#	 .	 -*	 "-	 3	 	 	 -1	 *	 3	 -	 3	 3	
*)	-		.	-1	1	3	=#	
	.	3	-<	433		
23.		3		3			23.	32	#)	3	-	54#2	3	
	
7.3.2 Acceptable Concomitant Medications 
+	-	3	3	*)		1	"		2N	4"	-1	.	-		3	
	"	3	*)		C2)	43	3	--#1		"	-			+	-	
-	 4	 .	 	 	 3	 	 2	 "-	 :
5;	 #)	 	 22<	 *3#	
:
;<	 3.	 #22-<	 	 *	 -	 	 "#	 	 "	 3)	 #	 #)	 3	 	 2<	
#-	"	#)	)<	"G#1<	#<			-1		.	#		3	
5	
	
+	-	-	*	43	!	1	."	3	"		"		-			1	"	
3			"		-			"	3		32	3#	.			
-	
-	-	"		1	"	3			"		-	3#	1	.		"	+	
	*		*	=1	
		"			!	
	
7.4 
Rescue Medications & Supportive Care 
7.4.1 Supportive Care Guidelines 
	3#	*	222	#22*		-#		-	1	.1	3	)	
*)	#)	.#		-		3	-	#	.4%	
	
7.4.1.1 
Diarrhoea 
	3#	.	"#1	-	"	)		1-2-	"%		
• 
	:3<	.-	2<	.		-##		<	43		43#	"*;		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
• 
>4	2"	:2	)		#;			
	1-2-	2<	"#	)	3#	.	#	#<		"	1-2-		2	6	
*<	2	*#	3#	.		
• 
	2	43	*		:@	;%		
o -./#-.	4	.		
			-	43	1-	
	3#	.					"				-)6C)61	"	2		G#*		
"	1-2-			-2*)	43	!	3#<		"=-.	?3	1-2-	
-2*		@			<		2	3#	.			#	*				
-3	
• 
	2	43	-		:@	;%	
o 	-./#-.	3#	.				3	-	3#	.			"	
1-2-		2	"	-	3		4C<	1-		3#	.		
:)<	 	-)6C)61	"	2		G#*;		"	1-2-			-2*)	43	!	
3#	"	)		"	)		<		"=-.	?3	1-2-	
-2*		@			<		2	3#	.			#	*				
-3		@#	"	#)	-	43	2-./#-.		.	"#		+22=	
 	
+	2	43	=2	3	3#	.	*		C	.	G#	"		"#		"	#""	
	"#	C			".<	"#		1	3#	.	#.#	*	*	"#	

7.4.1.2 Nausea/vomiting 
$#		*-)	3#	.		))*1<			3#	.	)*		#.G#	1	
	3	-	"	2231	-	321	)			#	2			
3#	.	)1	#)		-	.		"#	C	
	
7.4.1.3 Infection 
	 43	 	 #-	 "#	 -2	 3#	 *	 	 	 *	 .	 	 3	 
"*	 )	 	 	 222	 .1	 3	 )	 *)	 "	 	 )*	 "#	 <	
)			#	2	
	
7.4.1.4 Immune-related adverse events 
			' 		.		.4		3	2	)#	#-		3	-*	.	
))	)		-)-	"	*	=2	"		2	--#)	)1			
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
7.4.1.5 Management of infusion reactions 
+#	 "#	 	 :433	 	 #	1C	 	 1-<	 )-<		 231=;	 	
""	"-	)6312*	<	3#)3	-	"	3	-"		--		.3	
+	 	 )	 	 1-2-	 ##1	 *2	 #)	 	 31	 "	 #)	 "#	 	 )1	 *	
-21	 43	 	 3#	 "	 -2	 "	 "#	 )61-2-	 -1	 #%	 +)	
6312*1	:#)	#)	"*;R	+3)	:,	2;R	>32-R	
#)3R	//R	
12	 :3	 "	 .3;R	 5)#	 :3<	 3)1<	 -;R	 03R	 012R	
012R	1)	:-#	2;R	$#R	##63)R	36G#-R	)63R	4)	
:23;R	31R	#-#	2	:		=.	"	#-#	2	#		-;R	9	
:3*<	4<	43;R	-)	.	(	.4	34	-	)#	"	2	43	=2		
"#			43	-	"	2-./#-.	
	
7.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related 
Events of Clinical Interest (irECI) 
--#	+*	*	:+;	-1	.	"			+	"	#C4	)1<		43	#)	
=2#				43		--#	23-		+	-1	.	2	.		3	#	"	3	
2-./#-.	-2#<		-3-	"	<		2	=2	43	--#32	3	
3*	 	 -	 -3-	 "	 	 	 2	 	 3#	 .	 2	 	 +	 3	 -1	 .	 #))*	 "	
2	 +	 	 +	 +	 	 #	 31	 "	 3	 "	 	 	 *	 -3	 "	 3	 	 	 "	
-		"		+		#2<	""	3#	.	-		#	#	<	"#<	-.<	=		
3	)	#	2		.)		+			+			43	*2		@			3)3	+	
3#	.	#	--1	43	3	
3"	*)		)	
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 10. 
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
Table 9: Infusion Reaction Treatment Guidelines 
"/





=

@		
	R	"#	#2		
R	*			
	-)	"	*	)		
-1		#	3	2		
-	-1	.		3	2	"	3	
*)
	
$	
@	
G#	"#	#2	.#	
2	2-21		1-2-	
-	:)<	3-<	
$+<	<		"#;R	
2231	-		"	
K	Q	3

	$


+	222	-	321	-1	
#	.#			-	%	
	"#	
+3-	
$+	
-	
$	
	-)	"	*	)		
-1		#	3	2		
-	-1	.		3	2	"	3	
*)	
"	1-2-	*	43		3#	"	
22)	#)	"#<	3	"#	-1	.	
		 M	"	3	)	"#		
:)	"-		-763		 	-763;		
34	)	4	.	3	#	1-2-	
*		3	2	3#	.	2
-	"	3	=	3#		


+% /?
5


=


%


$$
%







	-1	.	2
-	 3	:X		
-#;	2		
"#	"	
2-./#-.	43%	
	
2331-	 	-)	
2	:	G#*		
"	3-;	
	
-	 	
-)	2	:	G#*	
	"	21;	
@			
@	%
)	:<		21	2*	
	1-2-	-	6	."	
#2	"	"#;R	#	"	
1-2-	"4)		
-2*-R	32/		
"	3		G#	:)<		
-2-<	2#-1	";
	
@	%	
7"3)R	2		*1	
#22		


	$
+	222	-	321	-1	
#	.#			-	%	
	"#	
+3-	
$+	
-	
$	
=1)	
	

	
223	
	
	-)	"	*	)		
-1		#	3	2		
-	-1	.		3	2	"	3	
*)	
02/	-1	.		





$$
%







	
$	#.G#	)	
+222	#	G#2-	3#	.	*.		3	-			231	1	*.	#)	3	
2	"	#)	-
5	5#3	"-<	2	"		3	
--	-)1	
	"	+*	*	*	 	:

+;	
	32%662)*
 
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 	"	((	
 
Table 10: General Approach to Handling irAEs 
"
)
%%;!

7@

 
@	
$	
*	1-2-	-	
@		
1	
433	
2-./#-.	
5	
#	
)	
	
2#-<	
2-./#-.	 3#	 .	 #	
2-1	

	 1-	 	 	 	 	
222	1-2-	-		2	
3#	.			1-2-	-2*		
@					2	*				4C	
>	 	 -	 	 "-	 	 #	 	
#.,	43	--#	*		
#	 	 .	 	 43	 	 #<	
-	
"	
3	
1-	
--##22		.	
@			
@		
?33	2-./#-.	
#	
"	
#.	
	
#	
	 	 	 K	 	 -)	 2	 1	
2	G#*	43		4C	"	
=1	
1-						
	 222	 1-2-	 -	 	 1	
#/				-)6C)	2		G#*	2	
1	
	
2	
3#	
.	
	
	
1-2-	-2*		@					2	
*				4C	
>	 	 -	 	 "-	 	 #	 	
#.,	43	--#	*		
#	 	 .	 	 43	 	 #<	
-	
"	
3	
1-	
--##22		.	


"	 	 +	 	 	 *	 	 -2*	 	 Z	 @	 	 43	 	 4C	 "	 	 -	 "	
2-./#-.<	#1	321	#	3#	.		"	#	43		C	
	
	*	3	
9		-)
	
	"	-))	2"	+		#--	.4%	
	
Immune-mediated pneumonitis 
	 #.,	 "	 )	 	 1-2-	 "	 2#-	 "	 2#-	 	 #2<	 *#	 43	
)23	 -))	 	 =#	 3	 #	 +-	 	 "	 @	 	 	 )	 *	
:		"		-)6C)61	2		G#*	"4	.1		2;<	433	2-./#-.	"	
-	 :@	 ;	 2#-<	 	 2-1	 #	 2-./#-.	 "	 #	 -	
:@	;<	*	:@	;		"3)	:@	;	2#-	
 
Immune-mediated colitis 
	 #.,	 "	 )	 	 1-2-	 "	 	 	 =#	 3	 #	 "	 	 +-	
	"	@		:"	2	"	L	1;		)	*	:		"		-)6C)61	2	
	G#*	"4	.1		2;<	433	2-./#-.	"	-	:@	;		*	:@	;	<	
	2-1	#	2-./#-.	"	"3)	:@	;		
 
Immune-mediated hepatitis 

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	  	"	((	
 
	#.,	"	3)		*	"#	:	3		"	-<	21	#)	-			
	.		 	 *#;	 	 1-2-	"	32<	 	=#	3	 #	"	32	
+-		:		"	 	8		-)6C)61	"	)		*<			8		-)6C)61	"	
)			)	*<	"	2		G#*<	"4	.1		2;	<	.		*1	"	*	
/1-	*<	433		#	2-./#-.	
	
Immune-mediated nephritis 
	 2	 "	 3)	 	 	 "#	 	 =#	 3	 #	 "	 23	 +-	
	"	)			)	*	:		"		8		-)6C)61	2		G#*<	"4	
.1		2;<	433	2-./#-.	"	-	:@	;<		2-1	#	2-./#-.	
"	*	:@	;		"3)	:@	;	23	

Immune-mediated endocrinopathies 
	#.,	"	)		1-2-	"	312231	:#)	3122#-		1		
#""1;		=#	3	#	"	312231	+-				1		
#""1		3	3-	2-		1	<	433	2-./#-.	"	-	
:@	;<	433		#	2-./#-.	"	*	:@	;		"	"3)	:@	;	
312231	
	
Monitor subjects for hyperglycemia or other signs and symptoms of type 1 diabetes. Exclude other causes of 
diabetes. Administer insulin for type 1 diabetes, and withhold pembrolizumab in cases of severe hyperglycemia 
until metabolic control is achieved. 
	
31		3*	.	2		#.,	*)	2-./#-.			#		1	-	#)	
-R	3"<	-	#.,	"	3)		31	"#	:	3		"	-<	21	
#)	-				.			*#;			)		1-2-	"	31	
	01231-	-1	.	-)	1-2-1	?33	2-./#-.	"	*	:@	
;	 31231-<	 	 2-1	 #	 2-./#-.	 "	 "3)	 :@	 ;	
31231-	01231-	-1	.	-)	43	2-	321	43#	-	#2	
	43#		5	#.,	43	*	:@	;		"3)	:@	;	231	
3	 -2*	 	 @	 	 	 4	 	 	 	 43	 3-	 2-<	 #	 "	
2-./#-.	-1	.		

Other immune-mediated AEs 
3	"4)		1	)"<	--#-	*		4	2			3	
M	:#	34	 ;	"	 #.,		 43	2-./#-.%	 #*<	 -1<	@#>^	
1-<	2		*	C		:M;			

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 '	"	((	
 
	
	<			"	+	3*		.	"		--#	*	"			:
;		"#	
	"	3		.	"#		.				! 		43	1-2-	
	3#	--1	
2	 *)	 2-./#-.	 	 .	 *#	 	 #	 #	 -	 	 #	 "	 3	 *	
*		*	=1	
	2*	"	32		3	#1	#)	3#	.	2	43		
3#	"	3	*)	.)	4		3	2	:*	
9;	43	4		#	"1		"	3	
	
	-		.		2	"		+22=	 	"	3	--		3	-)-	"	
3	
	"	3	*					.		43	3	#1	#)	3	231	3#	=	
*#		,#)-		3	*	-)-	.		3	2		+1		G#	"	3	
		"-		-)-	"	
	3#	.			3	2	:*	
9;	
7.6 
Supportive Care Guidelines for Pneumonitis 
	 43	 1-2-	 2#-	 3#	 --1	 2	 *)	 2-./#-.	 	 3*	 	
*#		3	*#	-1	#	.321		2#-1	"#			#	#	3	#	
#3		"		"	3	2		-		3*	#1	#)		2#-<	3	#))	
-	2				.		

Table 11: Recommended Approach to Handling Pneumonitis 






)
%%;!

7@

 
@		
:1-2-;
$		
*			
@		
?33	2-./#-.<	-1	
#		-	"	-2*	
	@			*	43		
4C	
	2	"	2#-	
8	#	2-./#-.	"	
#2	3)	3	2	
*2			2	"	
@			3)3	2#-

	2#-1	#	43	.321		
.216>+7	

#			2	*#	22=-1	4	2	4C	

	"G#	
3	I1		2	"	-)	
	43	1-					"				
-)6C)61	2		G#*	?3	1-2-	-2*	
	@			<		2	3#	.			
#	*			3		4C	

	.
@			
@		
#	2-./#-.	
'


	
>321	43	.21	6	>+7		--	
--1		43	*#		
:-312	 	-)	;	?3	1-2-	-2*		
@			<		3)3				:2				
-)6C)		2	1		=-3		-)	*1		3#;	
2	3#	.			#	*			3		
4C	
"			"4	.1	3)3						
#		1-2-	43	!		&3#<		43	
	"--1	-#	#		
"--1	-#	#2	1-2-	"				
2)		2	*	 		'	1	"	1-2-	
4	#)		#<			2)	"	
	)			3)3		"	!		-)	"4	.1		
-	2)	2		-		
"--1	-#<				2231	.	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 &	"	((	
 
"	22#	"	3	#	"	"=-.	-1	.	
		222
	
5	@		2#-	3	-2*		Z	@		43		4C<	3	"4)	#	3#	221%	
• 
5	2	"	2#-%	1		)	*	.1		4C		#.G#	1	
• 
	2	"	2#-%	-1	#	2-./#-.	"	#2	3)	3	
2	*2	2#-	≥	@		
	
7.7 
Diet/Activity/Other Considerations 
7.7.1 Diet 
	3#	-		-		#	-"		G#		-)		+	#3		3<	
#		*-)	
	
7.7.2 Contraception 
-./#-.	-1	3*	*	""			"#	 		5#3-<				C4	"	2-./#-.	
3		*	""		3	-2	"	2-		$2)<	.")	4-	-1	.	
	"	31		4)		#	3)31	""*	-3	"	2				3)31	#C1	
	*		0)31	#C1		*		"		;	#)1	<		;	2-2#	:	4-	
43	 3	 	 3	 -	 "	 	 -3	 43#	 	 *	 -	 #	 4	 .	 	
2-2#;<		;		3=#1	*	"	3	#	"	3	#1		3	.1	"	=#	
.			.	*#				3	#	"	3				3	2"		##	
"1	"	3	#.,			3#		#)	.3		"-	)	3#)3#	3	#1	2	
#2			1	"	3			"	#1	321		2	43	2	"	3	.)	2	4	
	.	G#		)		#		G#	-3	"	2	)	43	3	"		"	#1	
321	3#)3		1	"	3			"	#1	321	
3	"4)	2	-3			G#%	
• 

-.	:)		2))	);	3-	2		43	3.	
"	*#%	<	*)		-	
• 
))1	3-	2		43	3.	"	*#%	<	,.		
-2.	
• 
#	*	:9;	
• 
#	3-)	1-	:9;	
• 
>	#.	#	
• 
-	2	3)31	""*	.3		-3	2*	3	2		3		=#	
2	"	3	4-	"	3.)	2		22		3	3	*-	2	3	
*	-	-	"	3	#)	#	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 !	"	((	
 
• 
=#	 .	 	 	 3)31	 ""*	 -3	 1	 "	 "	 	 ")	 "-	 3=#	
#	#)	3		2	"	C		43	3	#1	-		
	 3#	 .	 "-	 3	 C)	 3	 #1	 -	 -1	 **	 #C4	 C	 	 3	 "#	
:#.	..1;	"	2)1	4		#	#)	3	#1					22		3	#1	31	-#	
3		3	2	G#-	:.	.*;	"	3	#	"	3	#1		#)	3	"4
#2	 2	 "	 3	 	 1	 G#	 3	 	 2	 4	 	 .1	 -21	 43	 3	 G#-	 "	
2<	3	2	3#		.			3	#1	
	
7.7.3 Use in Pregnancy 
"	 	 2	 *1	 .-	 2)	 43	 	 -	 43	 2-./#-.<	 3	 2	 4	
--1	.	-*	"-	3	#1		3		4		3	2			-31		#-	3	
2N	#	#	3	2)1	3	.	-2		-		3	#-	"	3	2)1	4	.	
2		3	2				43#	1		43		3#	"	3	#-			#	*	
=2	:)<	3<	.<	)	-1<		3	.)		"3)	-2		
3	-3		4.;		3	#1	*)	4	-C	*1	""		.	2-		"4	3	
#-	"	3	2)1		2	3		"	3	"#		4.		3	
9	43#	1	
	43		3#		3	2	:*	
9;	"		-	2	-2)	3	"-	2	3	#1	
2		3		-#	.	"-	--1		3	2)1	2		3	
9		"4	
	.	.*				!	
	
7.7.4 Use in Nursing Women 
		#C4	433	2-./#-.		=		3#-	-C			-1	#)		=		3#-	
-C<		.#	"	3	2	"	#	*			3	#)	"<	2	43		.
")			).	"	-	
	
7.7.5 Treatment of Overdose of IMP 
5	 2#2	 "	 3	 <	 	 *	 4	 .	 "	 	 1	 	 =)	 3	 2.	 	 "	
2-./#-.	 .1	 M	 *	 3	 2.	 	 	 	 	 !	 "	 "	 	 2)	
2#	
7.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study 
7.8.1 Permanent Discontinuation of Trial Medication 
+	2	-1	.	2-1	#	"-	3		-	"	1	"	3	"4)	%	
• 
3	#.,	434		
• 

"-	)23		2)<	2			 		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	 (	"	((	
 
/%	5	#"-	)23		2)	+	2	-1	.	)		=2	
	#		-	43	"-	)23	2)	"	1	.		1	
-2*	
• 
92.	*	=2	
• 
#		3	2*	"#3	-	"	-	
• 
3	2	3		"-	2*	#-	2)1		
• 
$-2	43		-		2#	G#-	
• 
+-*		
• 

-2	"	 	1	"	2-./#-.		
	2	4		.		-	3		3	2-1		"	#	3#	.		
	3	
5		3		-	3	.	#	3	2	3#	-2	3		"	-	
:"	22.;		"1	"4#2	*	2#				3	3#	"	#1	-	:.	;	
+"	3		"	-<	2	4	#		.		"	+		+	-)	#	-2	
"	3	"1	"4	#2	*	
	
	
54#2		"	2	#)	3				"4%	
• 
+	2	4	.	G#	%	
o +		"1	"4#2		1	"	3			"	2-./#-.<	
• 
"		2	+



31	4	.	G#	%	
o 9C	#**	#	-	*1		4C	#	3<	434	"	<		
	"4	#2		3		"	3	#1	
• 
"	 	 2	 #	 "	 	 3	 3	 2)	 #)	 -	 	  

+
%+
%

$+	31	4	.	G#	%	
o +	"4#2	-	*1	(	4C	#		2)<		"		4	
	 -	 3<	 	 "	 3	 #1	 	 "-	 ))	 2#1	 	
-	4	.		"	4	-			
	
7.9 
Withdrawal from the Study 
	3*	3	)3		#	#1	-	1	-	"	1	<	43#	2,#		3	
-	 	 ?34	 "-	 3	 #1	 "	 	 #	 "	 .3	 #1	 -	 	 #1	
-R	3		#		1	-	)		3	"4)	%	
• 
		
• 
7		"4#2	
• 
3	
• 
2	*)		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
	-1	434			1	-	"	1			3*		-	22		3		"	
3	*)	3#	1	#4	""	#			<		2	-1	.	434	.1	3	*)	
	3	2	"	-		3			222<	3		2		*<		"	-*	
6	3	"1			?3		2	#6434	2			-2<		22.	
*	3#	"	3	"		*	3#	.	2"-		3	-	"	#<	3			
	3	3#	"	#1	-	:.	;		+1	+	433		2		3	-	3#	.	"4		
	43	3	"1	G#-	#			!	
	
	43	;			-2	2		.;	-2	 	1	"	-	43	2-./#-.	-#	
#		-1	--	"		&	1	#2	#.G#		2)	-	
3#	.	#	43	3	
3"	*)<	3	2			-./#-.	-	4	.	
4	1	"				3	.		"	3	2		"	1	3	2*	""*	32#	2		
	*.		2		"			.		3	*)		#1		-		
2#	3#	.		"	3	.1	-./#-.		23	:	.	;				
		)	3		"-	"	)	-<	2*	3				3	-	#2	
*	"	3		"-	3	
	5-	+"	#)	-	"4)	-	
"	-2	2<	3	2	3#	#		3		"			1	"1	"4#2	*		3	
2		3	"4#2	2	"	3	#1	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
8 
PHARMACOVIGILANCE 
8.1 
Adverse events 
8.1.1 Adverse Event Definition 
+	 +	 	 "	 	 1	 #4	 #	 	 #2	 #	 :#)	 	"	 	 2
=)	-	;			2	-		23-#	2#		#C)		2
2"	2#	+	+		3"	.	1	#"*#.		#	)	1-2-<			
6	.1		231)	.*		43	3	#	"		-	2#		2
2"	2#	.#			1	3*		3*		#	32		3	-		2#	
+1	4)	:	1	1	)"	*	3)		"G#1	6	1;	"		2=)	
	3		-21		43	3	#	"	2-./#-.<				+ Changes resulting from 
normal growth and development that do not vary significantly in frequency or severity from expected levels 
are not to be considered AEs.  Examples of this may include, but are not limited to, onset of menses or 
menopause occurring at a physiologically appropriate time. AEs may also occur in screened patients during 
any pre-allocation baseline period as a result of a protocol-specified intervention, including washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  
 
8.1.2 Adverse Reaction Definition 
+	+		.1	3	2	*)		6		
3"	*)		.1	C1		.			
3	-	"		-	2#		22"	2#
8.1.3 Disease Progression 
	2)	"	3		#	#1					+	#	3	*)				
.				#		32		2)	=)	2	32		3	
	
8.1.4 New Cancers 
3	*2-	"		4		3#	.	)			+		2	)1		
	
8.1.5 Abnormal Laboratory Test Results 
+	1	-2	.-	.1		#	#)	#)	3	#1	4	.			+	
3	1	-2	.-	.1		4	.	2		222	*	#	31	#	
3		.				*	-	2.	.1	3	*)<		#		)	3	=2	3-	
	-			

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
8.1.6 Pregnancy and Lactation 
)1						+<	34*	3	*	3#	.	2		3	
9	
"4)	)#			!&	
8.2 
Assessing and Recording Adverse Events 
+	+	4	.		"-	3	-	"	3	"		#	3	"1	"4#2		3	
5	31	4	.	
"4	#2	)			2	#	3	*	3	.		*<		3	"4#2	*	3	
C	 2<	 433*	 	 3	 	 +	 4	 	 .	 	 3#)3#	 3	 #1	 3	 2)	
-"-	"	+	-)	1	#			.			!		
54#2	 "	 +	 43	 	 #1	 "	 2.<	2..	 	 3)31	 2..	 4	 #	 #	3	 *	
*<	.		3	2	-2	3			+1	#*	+		3	2N		*	3#	.	
"4	#2	"		)		-1	<	.#	43#	"#3	)		3	
5		
"		*)		"	1	+	3	363		#<	#)	3<		1	-	"		2	
3	-2	3	#1		363		3			.	2.1	3	3	*				
2-./#-.<	3	*)	3#	"1	3	
9	7	=	4	.			2		
43	3	+		
3	"4)		4	.			3	
5	"	3	+%	
• 
+	2	6	)	
• 
	"				"	#	
• 


+	)	-=-#-	1	
• 
#	
• 
*)	#1	)	)	3	#1	-	:1		;	
• 
=2	
• 
+	C	43	)		#1	-	
• 
#-
5	3	2)	2	+	4		.			2	3	3*		#)	1	2
2"	2#		*		"	3	2	G#		.	4<	"3	#-#	.21		"	3	
#1	3	3	2	4	.	G#				3	-	#1		+	4	.	2#		.	
.*	
8.3 
Evaluating Adverse Events 
+	4	.	*#	.1		*)	43			G#"	-	231	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
8.3.1   Determining AE Severity and Grade 
+	*1		)	4	.	*#	)		3	
--	-)1	"	+*	*	:

+;<	
*	 	+1	+	433	3)	

+	)	*	3	#	"		)*	2	3#	.			3	
	3	*1	3)			4	+			3	+		2	"-	"-	3			3	4	
*1	
8.3.2 Determining AE Causality 
3	*)	-#	*#		.	#""	"-			3	#1	"	3	+		-#	
2*	 363	 2	 433	 3	 *	 3	 1	 32	 	 3	 -	 #1	 -	 6	
2#	3	-1	G#	#)	#22-1	*)	"	)"	+	.		3		
,#)-	"	3	C1	#*	"	6	#	C)		"#3	2	"-		2		3	"	
"	3	+	

#1		3	32	"		+		3			4	.	-		"4%	
!$
	
• 
3			*		#))		#	32
• 
	43		-			3		-	
• 
$	.*#	*	-	=2
	
• 
3		*		#))		#	32	
• 
	43		-			3		-	
• 

	.	.1	=2	.1	C4	3	"	3	2N		
	
• 
+	#	32	.4	3			3	+					.	2.1
• 
	43		-			3		-	
• 
04*<	3	"#	"	3	"	-1	3*	.#		3	*	:)	3	
2N		<	3	-	-;
:,	
• 
3			*		#))	3			#	32	
• 
3		3	.	=2	"	3	*	:)	3	2N		
<	3	-	-;
• 
3	-			#3	3	3		#)			C1		3*	3			
43	3	.*	""



	
• 
3	+		"1			43	3		-
	
8.4 
Serious adverse events (SAEs) 
	
+	+		"		1	#4	-	#		""	3		1		3%	
	
• #		3R	
• 	"3)		2	3	2<		3	*4	"	3	*)<		--	C	"	3	"-	
3	*			#R	
• G#	2	32		2)	=)	2	32	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'	"	((	
 
• #		2		)"	21		.1R	
• 		4		
• 		)	-1		.3	"R	
• 		43		*	:433			;		+1	+		43		
*				+		
• 	1	3	-1	-2	*	
01""2$&111#1#.11%""11"  " %  
 3  ""   4"  "5  . "  .1  #5 %  1
1     #     "  %  "  # #  1""
"1& " "# %#&1"
2"# %# "151 .5  6 1#
" "(2$&15"  "7".51%1#7 "1"
 6 "  . % %1"%

8.4.1 Reporting SAEs 
+	+	)	"	#1<	2)1		*	3	#	"-	3	-	"		3#)3	(	1	
"4)		"	#1	-			1	"4)		"	#1	-	"	3	22	
		4		321<	433*		<	-#	.	2		3	+	2	"-	43		
3#	"	3	*)	6	)	.-)	4	"	3	*		
	
3	+6
	2	"-	3#	.		
-%	-_-33#C	
5=%		!( 	'&'	
43	4		#	"1		"	3	*	
	
3	+	"-	-#	.	-2<		"	#1		=2	)	3	#	*	"	3	
*)	 >3#<	 3	 )	 	 	 .1	 3	 2	 *)	 	 	 2221	 G#"	
)	 *#	 "	 	 3	 )	 )	 3	 2	 4	 3	 .	 *4	 .1	 3	 
3"	
*)	:		-	2*;		"-			=2	3	

+	*	
 	-#	.	#		)	3	+<		3	4	)			"	4		-	"-			
2*#1	2	+	.-	*.<	3	*)	3#	2	3		3	2	:*	
9;	
		4	+	2	"-	3	2	:*	
9;	4		#	#.-	3	#2	2				
"		3	+	-2	)#	"	"#3	"-		
	
+1<	1	+		.1		*)	43			G#"	231		.			3			
22"	2#	3		.#)3		3		"	3	*)		1	-	#	"	3	-	
2	2"		3	2*#	2)23		-#	.	2	--1		3	2	:*	
9;	
43	4	"-		
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	' 	"	((	
 
8.4.2 Events exempt from being reported as SAEs 
*	 2"	 	 3	 	 	 	 G#	 2)	 	 +	 	 3	 <	 #	 32	 	
2)	"	1			3		+	"-	-#	.	-2		3	*	-#		.			3	
222		"	3	
5			
1. *	-		32	"	2#	433	4	2		#-		3	-	
		3	-	"				+<				G#	+	2)			
2. 02	"	-	"	3	<			"	#1	2#	#3		
23-C	-2)	)		3		2<			=-2	"-	.)	2			
+	
3. )*						+	#	3	2	G#	2	32		
2)	=)	2	32		3	.#	4	.	2		3	
5		
8.4.3 Determining SAE Causality and Expectedness 
Assessment of causality and expectedness for all SAEs will be made by the PI/designee and Chief 
Investigator or delegate against the Investigator’s Brochure (IB) (Reference Safety Information contained  
within the  IB).  If updated versions of the IB are released during the course of the trial then assessment of 
expectedness will be made against the current regulatory approved version. The IB as last amended and 
approved by the national competent authority serves as the reference safety information for the assessment of 
the expectedness of any adverse reaction that might occur during the clinical trial. The expected side effects 
from thoracic SBRT include: Shortness of breath, cough, chest pain (including rib fracture), skin reactions 
where the beams entry the body, tiredness, pain on swallowing, scarring and local inflammatory changes 
around treatment site and longer term reduction in breathing capacity. 
	
8.5 
Events of Clinical Interest 
8.5.1 Definitions of Evidence of Clinical Interest (ECI) 
	#		+			.	"		*	"	
		:
;		*		
*	=1	
		-#	.	2		.			! 	
*	"			"	3		#%	
1. +	*	"	2-./#-.<		"			0	3				43		
1-2-		.-	.1	#		
2. +	#)	#	*	,#1	:7;	"		*	+		+7	.	*#	3		)	3		
G#		I	3	#22	-	"	-		
 
 
 
AND / OR 
 
An elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal  
 
 
 
AND / OR 

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	''	"	((	
 
+	C	2323	.	*#	3			3	I	3	#22	-	"	-<		-	.1	41	
"	22"	.1	)		#3#	.1	)	
3. +1	+	"		3	.4	.			.	"		--#	*	"		
	+		*	"	*		*	=1	
	3#	.	2		.		
	! 	
	
	3#	.		"	2.	
	2		3			7.	#	3#	.	*#		2	
3#	.	C	"	)		1-2-	#))*	"		--#	*			43	*2		
	
3#)3		.	--#	3#	3*		)		#	#	3	)	#		"	.	#	
	1-2-			2.	--#	
<	3		)	3#	.	2"-		#	#	
3	)	#		"		3	#		"#<	3			#-		.	--#		
8.5.2 Reporting of ECIs 
*		*	=1	
	433					3	2-./#-.<	#)	"-	3	"		
#		1	"4)	3		-	<		3		"		4		321<	433*		
<	-#	.			3	+		2	"-		2	#)	3	+6
	2	"-	43	
	3#	"	3	6)	.-)	4	"	3	*		3	2	:*	
9;		"4%	 
	
The SAE / ECI report form should be sent to		
-%	-_-33#C	
5=%		!( 	'&'	
43	4		#	"1		"	3	*	
	
?3	2)		
			*	#)	3	+	2	"-<		3#	.	"	433			3	

		*					+	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'&	"	((	
 
6?	--#		+		
	
 

  

		
 	!"#$
+#		#-
	7#)		
#-

  

		
 	!"#
		
			


	

	
$
	.#

		

	-2

3-3)
@	2"
$)	
3


		
 	!"%!"#
		
			



	
	
$
+	#""1		
01231-
012231
0122#-
01231-
31	
31	
012)1-<	"	J@				43	C		-.		
:F+;
12		.	-#	:"	4	;	
'
	 

		
 	!"%
		
			



	
	
$
+#--#	3-1	-	
+2	-	
3-.	3-.12	
2#2#
23	3-.12	
2#2#
-	*#	
)#
0-1	#-	1-	
+1	)		-	)	"	#1)	-3-
'
  

		 
   	 ! " #    
	 	 
 			  
 


	
	
$
02	
+#--#	32		
-	
*	
:+6	
+;
	$
  

		
 $
+)	
+231=

1C		1-	
#-	C
"#		
"#C		
 

		
 $
+#--#	#231	
@#>	1-
-1)	21#231	
13	1-
 

		
 	!"#
		
			


	

	
$
9*

 

		
 !"#$
$23
$23	#--#
	5#	
	"#	#	

	*		:2		
	"	!"%
	
	
			


	
	
$
,

		
 $
-	="
13-	-#"-	
*B3	1-
=	2-	1	
,

		
 !"%$
##
3
3	)		
3	-#22#
+1	3		)"		3	231	,#)-

% 

		
 $
1	


+1	3	)		*	433			--#	.1	3	231
	
 
 

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'!	"	((	
 
8.6 
Definition of an Overdose for this Protocol and Reporting of Overdose 
+	2		2"	"-		*.		3	-	"	*	"	2-./#-.	5	2#2	
"	3	<		*	4	.	"		1		=)	3	2.		"	2-./#-.	.1	M	
	3	*	"	*	3	2	3#	.	.*	1	"	)	"	=1		+222	#22*	
-	3#	.	2*	"	1		
	
"		+:;			43	:O#	"-P;	3	*	"	2-./#-.<	3	+:;	3#	.		
	3	+	
5		2			+<	*	"		3	#			-		
	
"		*		C	43#	1			1-2-		.-	.1	#<	3	*	
	)				+		3	
5		2			#	
<	#)	3	-)1	O	
		*	43#	*	""P	
	
+	2	"	*	3	+		
	-#	.	2	43		3#	"	3			)	.-)	
4	"	3	*		3	2	:*	
9;		"4%		
The SAE / ECI report form should be sent to 
Email: MesoPrime.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 
	
?3	2)		
			*	#)	3	+	2	"-<		3#	.	"	433			3	

		*					+	
8.7 
Reporting of Pregnancy and Lactation 
+3#)3	2)1						+<			3	2.1	"	*)		3	
)		2	1	2)1					2	:2#1	2		3-;<	3	#	
#)	3			43		1	"	-2)	3	<			1	"4)		"	-	"	3	
2		4		321<	433*				+	2	43	.-	2)	-#	.	
"4		3	-26-	"	3	2)1		)1	#-	"	2#	.<	
-	.<	.)	31"-	-<	.)3	*#-<	"	3<	#	3<	-)		
	.3	-#	.	2		+	:-2		*;		"	3	2)1	#		-<	3	
#-	:33	"	";	-#		.	2	43	3	2N		#3	*	-#	.	2	
43		3#		3	2	:*	
9;		"4%		
 
The SAE / ECI report form should be sent to 
Email: MesoPrime.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 


	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	'(	"	((	
 
	
8.8 
Definition of a Serious Adverse Reaction (SAR) 
+	+		"			+	3		,#)		.			1		"	#1	#)	-		3	2	
	
8.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) 
+	9+			#	*	<	3	#		*1	"	433				43	3	22.	
2#	 "-	 :)	 "	 "1	 "-	 22	 "	 *)N	 .3#	 "	 	
##3	*)	2#		#--1	"	2#	3	"		#3	2#;	
8.10 Reporting of SUSARs 
+	9+	-#	.	2	#)	3	+	2	"-	43		3#	"	3	6)	.-)	4	
"	3	*		3	2	:*	
9;		"4%		
The SAE / ECI report form should be sent to 
Email: MesoPrime.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD, relevant Independent Ethics Committee (IEC) / Institutional review, 
appropriate regulatory authorities and the participating Principal Investigators of the event. 
	
3	2	:*	
9;	4		#	"1	3	<	*	2	3	
--	:
;	6	
#	 *4<	 222	 )#1	 #3	 	 3	 22)	 2	 *)	 	
	43	)#1	G#-		43	3	-		"	.4%	
• 
5	"		"3)	9+	3	2	:*	
9;	3#	2			3	--#-	
"-				2.			1				3	*	1	"	.)	-	4	"	3	
		
• 
9+	433			"			"3)			.	2	43	 	1	
54	 #2	 "	 2	 43	 3*	 =2	 	 9+	 3#	 #	 #	 *1	 	 -2	 	 3	
	3	.	
8.11 Annual Reporting of Serious Adverse Events 
3	*2-	"1	92	2	:9;	4	.	#.-	#1	43	'	1	"	3	*1	
"	)#1	22*	"	3		3	2	4	.	#.-		)#1	#3		2	
3	
--	:
;			43		22.	).	4		)#	3	9	4	.	
22	.1	3	2		.	43	
9		4	.	#.-	.1	3	2		2	4	
.	"4		
9<			*)	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
8.12 Urgent Safety Measures 
3	2		*)	-1	C	222	#)	"1	-#	:9;				2	3	
2	"				)	1	--	3/		3	33		"1		3	#	2#	
C		2	2	"-	2-		"	3	2	#	C		3#-	33		
	
9	-1	.	C	43#	2	"	"-	3	-2	#31	04*	3	
6)	-#	
"1	3			03	#	)#	:0+;<	3	3	3	
--	:
;	
	3	2	:*	
9;	"	3	4	*		3	-#	C		3	2	"	"#3		
43		1	"	3	-#	.)	-2-		3#	3				9<	3	*)	-#	"-	
3	2	:*	
9;	--1	3	.1%	
 
Email: MesoPrime.Trial@rmh.nhs.uk  
Telephone: 020 8642 6503 
Fax: 020 8915 6762 
 
	
3	"	-#	#%		
• 
3		"	3	9R		
• 
?3	C	3	R			
• 
?31		4	C	
	

9	4	"1	3	0+<	
		3	2	--1	.1	23		43		1		4)	
"	9			
9	4	.#	3	2		1	#.G#	--		3			
	
Chief Investigators Contact Details: 
Name:  
Dr Fiona McDonald  
 
 
 
Dr Stephen Harrow 
Address:  
The Royal Marsden NHS Foundation Trust  
Beatson West of Scotland Cancer Centre 
 
 
Downs Rd 
 
 
 
 
 
1053 Great Western Road 
 
 
Sutton SM2 5PT 
 
 
 
 
Glasgow G12 0YN 
Email:  
"-_-33#C  
 
 
2334_))3#C  
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
9 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
9.1 
Statistical Analyses 
3	"	1	4	.	#	"		"	3	"4)			-	
`	
3			-	1	:"	=-2<	#		=1;	
`	
+	2	3*	3	3	22#1	"	-		3*	-2	3	Y""#1N	*	
		"	3			-<			#""		4	.	.3	+	2	*	#)			
."	3		4	.	1		#--		3	"		#1	2	+1			"	
3		4	.	#--			#22-	2	
	
+		4	.	1	#)	3		"4	++	*		D#*		4	.	2	
	 #-.	 "	 .*<	 -<	 	 *<	 --#-	 	 -=-#-	 *#	 "	 -1	
.#		-<	G#	)		222	
)		4	.	2		"G#	
	22	?3	222<		4	.	2	3	43	( M	"	*		=	
.-	"	*	>	3	4	.	#--	"			2		
43			434	."	-					-2	3	G#	"1	.*	4	.	
.	 	 *#	 21	 -	 -	 4	 .	 .	 "	 	 1	 	
-<		-"		1		3	#	"	321	4	.	.	
	
9.1.1 Primary Endpoint 
5	 3	 2-1	 2	 "	 .3)	 3	 >	 	 @1	 	 H	 	 	 	 .	 "1	 -.	 43	
2-./#-.<	3	=1		4	.			3	22	"	2	43	3*	3		7	#	
)	43		=	.-	"	*	+	=	4	.	.#	.1	12<	)			*	
3	4	.		"		+ 
	
9.1.2   Secondary Endpoints 
+#			=1		4	.	.#	.1	12<	)			*	43	3	#-.<	22		
"G#	"	)			)		)	2	3	#	"		."		.1	*	
2		:;	"		-2	2	:
;		2	2	:;					
:
;	"		
<			.		:;	#)	-"	
	:+22=	';		
		4	.	
#			22	"			43		( M	"	*	2		:		
;<	
4	.	#		22	"		2			3	23		-	3)	#.12	
)*)		( M	"	*	+1	""		2		:"			"	
;	.4	
3	4	#.12	4	.	-2	#)		3	G#		53N	=			222	3	4	.	
*#	"		+			>		"	*	7	)		"			#-#	22	<	
2			2)	"-	8M					4C1	2*	:	8	(M;R	)1	2*	"	L MR	
	)*	"	KM 3	""	"	7	=2		2		4	.	-#	#)	3	22	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
"	2			.	4C1	2*< strongly positive or negative			#)		
3	G#		53N	
=		"	22		=2	*	.4	2		2	5	4	.	-#	
"-	 3	 	 "	 321	 #	 )	 	 	 *	 "	 2)	 	 3	 	 4	 .	
			"		"4#2	"	#**)	2		4	.	-#	"-	3		"	321	
#	3		4	.				"		"4#2	"	#**)	2	#	"	2	:;	
4	.	-#	"-	3		"	"	2	#	)			*	"	2)		3	
	 4	 .	 	 	 	 "	 	 "4#2	 "	 #**)	 2	 	 5<	 	 	 	 4	 .	
#	#)	F2	-3	)*)		( M	"	*<	2*1	5<			
			'			-3	4	.	2	43		( M	"	*	5<				
4	.		"	*			+			>	-.	9	34	<		1	2	
4	.	1	"		+<		>		*	
	
9.1.3 Exploratory Endpoints 
=21	2	4	.	2			2*	"3	?	4%	
• 
.	3	2	"	7		#-#	)		3*	#-#	.2	3	
--#33-1	1	4	#<	.#		1	.	-	<	3	"4)	
-C%	
<	
!<	5I2<	<	7<		7	
• 
>	4	.	1	"	$+	2		2	> 	
=21	2	4	.	1	"		+<		>		*	
 
9.1.4 Timing of analyses 
=1		4	.	*4	.1	3	"1	*4	
--	"	*1	3	2		3		3	
:	3			3	'3	2;	3	-2	3	7	2	2		1		))	=2	
23		
	+		.	1		3		2			"1	3	3	-2	3	7	2	433			
4C	"-	3			"	#)	>	:		
';	5	2	+		><		"	-		#		
2)<		#2.	=<		3	2	434			3			43	2	3	
-2	 	1	"	-		"	#1		43	3		2	3	-2	3	""#1		3	
"	"4#2	*<	433*	322		
9.2 
Sample Size 
#)	3		+<			S	)	4	.	#		#	2			>		3	"		@1	
	H	43	2-./#-.			"=		*	3	-	3	3	4	.		--#-	"			-=-#-	
"	'	2	G#	"		+	3	4	3	.				2			><	"	3	=2	
23	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
10 REGULATORY, ETHICAL AND LEGAL ISSUES 
10.1 Good Clinical Practice 
3	#1	4	.	#			43	3			22	"	@
		"		3		
	)#	
10.2 Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
>"	)	3	<	3	2<	2	"-	3<		"-<	1	3	4	"-	
3	4	.	 2*		 3	2	 	 1	 *-	3	 4	.	 #	 	 	 "	 1	 2	
-2	-#	.	22*	.1	3		
--	"	
	3			22*<	3	#1	4	
3	.	#.-		3	*	3	
--	"	3	*4		22*				3	32-	"	
		3	)	1	2	3	*)		3			2.	"	1		2"	-	
	.)		E	22*	"	3	#1	+	22)		4	.	G#		)		)-	
43	
9	433	#	G#-		)		3		3		2	
 
+1	2	--	3#	.	)	43	3		-)-	)#2	:@;		.	22*	.1	3	
2	2		#.-		*4	.1	3	*	3	
--			"*#.	2	"-	
	
3	.	.	3	--		.	.#				-2-				3	2.1	"	3	
2	 *)	 	 #.-	 --	 	 3	 E	 2-	 "	 E	 22*	 +--	
G#)	
	22*	-1	.	-2-	1	"		21	"	3	
6>N	22*		3	.	
.	 +--	3	 	 		-	 	 22	 --	 3/		2	 -1	.	
-2-	 2	 	 *)	 2	 	 
6>	 22*	 04*<	 	 3	 <	 22*	 -#	 .	
.				2.	"	-2-	
10.3 Annual Safety Reports and End of Trial Notification 
		3	2.1	"	3	2		#.-	3	*2-	"1	92	2	#1		3	0+	
6	
	43	'	1	"	3	*1	"	3	#	0+6
	22*	3	4	"	3	#3	
#)	*4	"	3	#1	3	#3	4		.	"-	"	3		"	3	#1	.1	3	2	
:*	
9;	43	(	1	"	3		-2	
2	"	3	2	4		.	3	43	3	-	
	-	"	
10.4 Regulatory Authority Approval 
3	#1	4	.	2"-		-2	43	9F	)#1	G#-	
		+#3	
:
+;	"-	3			03	2#	)#1	+#31	:0+;	4	.	.	2		
3		"	3	#1		<	3	0+	-#	22*	--	:	#	.1	3	2	:*	

9;;<	*	9+	2		#	"1	#2<		.	"	"	3		"	3		
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&	"	((	
 
10.5 Notifications of Serious Breaches to GCP and/or the Protocol 
3	2	:*	@
	
-2	-;	4	"1	3	0+		
		4)	"	1	#	.3	
"%	
a. The condition and principles of GCP in connection with the trial. 
b. The protocol. 
3	 4	 .	 	 43	 &	 1	 "	 .-)	 4	"	 3	 .3<	 	 	 43	 3	 22.	 9F	
)#		-	"-	-		-	
5	3	#2	"	3	)#		O#	.3P			433		C1		""			)"	)%	
a. The safety or physical integrity of the subjects of the trial; or 
b. The scientific integrity of the trial. 
1-		2	-2	.1	3		43	@
	6	3	#1	2<	#)	"#		
2	+	#)			43	3	2"	-"-<	-1	.	-		#	.3	
	
10.6 Insurance and Liability 
3	 2	 3	 #	 -1	 "-	 3	 -#"#	"	 2-./#-.	 "	 2	 	 	 	
*		""	"	-#	,#1	-1	"	22)	32		2*	.1	3	##	
$0	 -1	 )-	 "	 	 ))		 +	 21	 "	 3	 *	 #	 216-1	
3-		#--1	3	.	2*		G#	
10.7 Contact with General Practitioner (GP) 
		3	*)N	2.1		"-	3	2N	@	.1		3	3	2		C)	2		3	
#1	2*	3	2	)		3<		"-		3	""		#		3			
5	+	21	
"	3		3#	.	"		3		5	+	-2		22*	.1	3	
6>	4	.	2*	.1	3	
2	:*	
9;			22)		
10.8 Confidentiality 
3	
3"	*)	-#	#	3	3	2N	"1		-		-2	43	3	9F	
		+	"	((!			3	
5		3	#-	#.-		3	
9<	2	3#	.	
"	.1	3				2	#1	#-.	1		
	
	 -2	43	 @
	 )#<	 	 	G#	 3	 3	 *)	 	 #	 2-	 #3	
2*	"	3	2	:2N	;		"	3	)#1	)1:;				*4	3	
2N	)	-		"	*"	"	#1	2#					#	
=-)<	1)<	*"1)<		2#)	1			2	3		-2		3	*#	
"	3	#1	3	*)		.)		"-		.	3		"	3	2		2-	-	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	& 	"	((	
 
2*		3*			363	#1		43#	*)	3	"1	"	3	
2		
	
+	 23-)	 -2	 	 3	 "-	 	 43	 3	 -2	 4	 .	 	 	 	
2221		#	"1	"	3	2N	"-			.	#	"	3	-2	
"	G#				3	*#			=2		."	3	2	1				3	-	
#<	3	#	4		.	2		3	2N	-			4		.	-	*.		--.	
"	3	"-1<	3	2	231<		3	3	2<	=2		2"		3	"-			
	
10.9 Data Collection and Documentation 
		3	*)N	2.1		#	3		*			1			3	-			
3	*)	-#	4	3	
9				*	#	#-	"	*"	"	
	 	 	 3	 
5<	 C)	 	 #	 	 2	 )#	 3	 	 	 3#	 .	
		3	
5		3	"4)	-#	.	*".	.1	3	#	%	2	<	-	31<	
2N	 ).1	 "	 22	 	 3	 <	 #1	 -	 -	 :2-./#-.	 	
321;<	#	3-)1		.3-1		2		-	
	
3	 2N	 -	 <	 	 3	 *	 <	 -1	 	 .	 *4	 .1	 222	 G#"	
2	2	"-	3	2	:2N	;	22		#	3	<		.1	
			
4	-	"		2N	-	4		.		#	3	32	
3	2	*)		3			"-)	)-	43	363		$0	#		#%	
• 
#""				"	2		.	#	C)	.4	32			
5		
• 
#						#-		#<	-2<	-		.	"	
-)		#	*		
• 
)		"-				)	.1	.3	2		*)			C2	)3		
		)	)3	43		21	"	3	2"	2	"-	3:;	)*		3	-	"	
		
• 
		#-	-#	.		"	3				-21	43	#	)		
$	#1	#-	4	.	1	43#	2	4	)-	.4	3	2		3		3#	
3		43		)	3	#1			3	21		-*	3-		3	<	4	)-	
-#	.	.	"-	3	2	
10.10 End of Trial 
3	Y"N		"		3		43	3		2	3	-2	3	Y""#1N	*		3	"	
"4#2	*<	433*	322			

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&'	"	((	
 
11 DATA AND STUDY MANAGEMENT 
11.1 Source Data 
+	"-		)			"	2	"	)		"		")<	.*<		
3	*					1	"	3	#		*#	"	3			"		
#		#					#	#-R	3		"		)	#-<	<	
		)<	32	<			""	3<	.1	<	--<	2\			
*#	3C<	23-1	2)	<			"-	#-	#-<	2		
2	 "	 "	 *"	 	 .)	 #	 2<	 -"3<	 23)23	 )*<	
-"-		-)	-<	=1<	2	"<			C2		3	23-1<		3	.		
	-3	2-	**		3				
11.2 Language 
+	 
5	 4	 .	 	 )3	 @	 -	 "	 -	 -	 3#	 .	 	 	 3	 
5	
43*	2.	+	4	-		.	#	.1	2	-#	#	*.#1	3		1	#<	
	.		3	)#)	222	"	3	#1		
11.3 Data Collection 
3	-	6-		3#	.	1	-C		4	1	"	"		2N	
22		3			3	*)	:	)	--.	"	3		#1	-;	-#		
		)		2	2#<		-<	.1	<	"1			""1			
3	
5		
11.4 Recording of Data 
N		4	.	#-				2"	
5	)	.1	
9	92	))	3	"-	
	"-<	3	2		)			"	#-.	
	
3	*)		2.	"	#)	3	#1<	-2<	1		-	"	3		
2	 	 3	 
5	 	 1	 3	 *)<	 	 3	 2	 43	 3*	 -2	 3	 #1	 -	
2.	)#	7)6)	7)		#3	.1	3	<	3#			3)			3	

5		+	2	G#	*)	-#	.	2		3	
5		3	*)	-#			
)	2<			-)	"-	3	*)	"	"##	"		3		4	.			
	 	 	 .	 :	 ;	 433	 	 24	 2<	 43	 #	 2"	 24	 4	 .	
2*		"		2	434	"-	3	#1<	3		-#	.			3	
5		
	
3	
5	4	.	)	.1	3	*)		.1		#3	""	--.	#1	2"	"-	4	
.				
5	*	.1	*		3		*	3#	.		43	3	#	#-		
3	2	3#	.	=2	+	
5		3#	.	1-#<		"	.1	#1	2	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&&	"	((	
 
#-.	1		3	2		Y""	#1N		3	
5	3	.	"#1	-2<	3	*)	-#	
2*		)#		#3	3	-2	2		
	
11.5 Data Management 
	-)-	4	.		#	.1	
9	#)			.				43	3	
	-)-	2	)	.1	3	
9		9		1	4	.		#	.1	2221	
	2		22)		D#	4	.		1	.1	3		-)	6		-	
			3	22)		"	#		
11.6 Study Management Structure 
11.6.1 Delegations of Responsibilities 
3	 	 	 2	 .1	 3	 1	 	 $0	 5#	 #	 	 3	 	 4	 .	 #	 	
	 43	3	2"	 )#1	 	G#	 "	 --	 3	 	3	 $0	
#	3	3	)*	"-4C	"	33					)		2		3	"4)	
2.	3*	.	)	%	
	
11.6.1.1       RM-CTU 

9	 3	 *	 2.1	 "	 ")	 	 )	 3	 #	 "	 3	 	 	 	 	
2.	"	)		.<		#C)		2)		1		
3	2.	"	
9	"	3	11	-)-	"	3		4	#	3	"4)%	
• 
#)		222	3	2	3	.	#)3<		1	--	3*	.	22*		
• 
@*)		"	--		2<	-C	2	.#	--		3		
	
	0+		22.	
• 
$"1)		3	3		3			
• 
)		*)	G#	43		*)		
• 
F2)		"		+<	*	<	2)		*		*	=1	
N	
2	.1	*)		
• 
$"1)	3		
<	0+		*)	"		+	

11.6.1.2 MSD 
• 
*	"	2-./#-.		#1	#22	

11.6.1.3 Participating Sites 
• 
#)		C2)		2	)-		3		3	22	"	@
		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&!	"	((	
 
• 
F2)		21	"		Y	#-N	:	"	#	3	22	"	@
;		#)	
222	3*)	"	#-		3		3			
• 
C)	222	#)	"1	-#	
• 

	43)		#		3	#1	4	.	C		2*	*	3	31		*	2	
-		
• 
2.		"			)-	.4		*#	22)			
9<	
433	-#	.	)			2	."	#-		--		
	
11.7 Protocol Compliance and Amendments 
+	22)		4	.	G#		)		)-	43	
9	433	#	G#-		)	
	3		3		2	
+1	2	--	3#	.	)	43	3		-)-	)#2	:@;		.	22*	.1	3	
2	2		#.-		*4	.1	3	*	3	
--		0+	43	G#			
"*#.	 2	 "-	 
	 	 "	 22.	 3	 0+	 3	 .	 .	 3	 --	 	 .	
.#			-2-				3	2.1	"	3	2	*)		#.-	--	
	3	E	2-	"	E	22*	
11.8 Trial Management 
3	
9	4	.	2.	"	3	11			-)-	"	3		3	#	
	#	)		"1	2)		"	22.			)-	4	.	)	.4	3			3	
2			*		22*			2			:*		";	4	.	#		
	<	)		))	*	4	.	2*	.1		)	4C32:;<				
))		#22		3	22)		.1		)-	@#2	:@;			
	
11.9 Safety Review Committee (SRC) 
+	
	4	.		#2		--.32	4	#	
3"	*)<	
*)<				
	)	*)		3	C1	#1	2	4	.	*		,	3	
		222	3	

	 3	 2	 2.1	 "	 3	 #	 "	 3	 	 3	 
	 	 2.	 "	 -)	
#-<	"1		)*	"	3			4		.)	43	#.G#		#.
#	3		4		*4	1	"1				*		-)	"	3	
	"	)"	
	=	
3		"	3	
		%	
• 
*4	*	"1			-C	3	=2		"		#	
• 
*4		+		-))	"1		.3	"-		2	#		=	9+	
*	"-		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	&(	"	((	
 
• 
	2)	"	3			#	-))	"1	"-		*#		2		
@
	22		3			
	
11.10 Monitoring 
#)	3	<	3	2N			2.	"	-)		G#1			43	*	
	2)	2#	:;		-)		4	.	-	"	2	-2		"	1	
	 	 -)	 	 	 "	 G#	 4	 .	 	 	 3	 	 "	 #	 	 +1	 1-	
	-1	))			-)	*	3			4	21	=-	3		
"	-		#<	#3			"4			-1	*	D#	4	.		.1	3			
	 #3	 #	 	 --#	 43	 3	 	 -	 4	 C	 2	 	 <	 	
-)	"	###					4	C	2	+)<	3	4		G#	*	3		
	
	
"			-)	*		G#<	3	2N		4		3			)	*			
3		-#	#	3	*		"		2			*.	"	*4		3	2N		
#)		-)	4	*4	3	*)		"		1	#	#		*"		
"-	-2	43	3	2<		)-	
	
11.11 Quality Control and Quality Assurance 
D#1	
	:D
;	4	.	2"-	)		
9		2#	3	#1	-1	.	#	
.1		D#1	+#	:D+;	2*	"	3	2	+	1			#-	4	.	-	
*.	"	2	
	
11.12 Clinical Study Report 

		4	.	2		3		"	3		.		"		)		3	
	)3	43	3		
	4	22		."		#1	2	6	2#.	.		3	"		)		+	#--1	
"	3	2	-#	.	2*		3	3	3	
--		3	0+	43		1	"-	3	
#.-	"	3		"		"	
	
11.13 Record Retention 
	#-		#-	3	*#1		*1	2-	*#	"	3	#	"	3	
		#.	3	G#1	"	3			#)	3				"		#	3	
*)	-#	-	G#		#			.	.3	3	#	"					
3	G#1	"	3		2#		.	*#		*"			43	#	)			
	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 

9	4	-		#-		"	3	-)-	"	3	<	#		2		
	43	1		@		2)	#			-2	43	3		
	)#1	G#-	
3	-	"	"		#.,	3	.				43		)				
43	3	-=-#-	2	"	-	2-	.1	3	32<	#		2*	2	+	-		
	5	#-	4	.		"		--#-	"	 	1	"	3	#1	3	#	
	
11.14 Reporting and Publication 
3		#	4	.	#.-	"	2#.			*	-	,#	43	#332	)		
3		"	.1	3	
B	:32%66444-,);	3		3	#332		3#	.	.	
;	#.	.#		2		)<	G#	"	<		1		2	"	
R	;	")	3			*)		1	"	-2	#	R		;	"	22*	"	
3	*		.	2#.3	+#3	3#	-		<	<				
"	2#.	:-#2<	.<			2;	3#	.	#		3	*	2		
4	#""	-	"	*4	2		#.-	3	4	.		""	: ;	1	2		*4	.	
	2			31	:;	1	2		*4			-#2		2		3	#3	43	1	
*	
	

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
12 APPENDICES 
12.1 Appendix 1 – ECOG Performance status 
	
$-	*1	5#1	*<	.		1			2	2"-	43#	
	
	
1-2-<	 .#	 -.#1	 	 	 2311	 ##	 *1<	 .#	
-.#1	 	 .	 	 1	 #	 4C	 "	 	 )3	 	 1	 #	 :)<	 )3	
3#4C<	""	4C;	
	
	.	K M	"	3	-	+-.#1		2.	"		"<	.#	#.		1	
#	1	4C	*	92		.#	-	3	 M	"	4C)	3#	
	
	.	L M	"	3	-	
2.	"	1	-	"<	"		.		3	
-	3	 M	"	4C)	3#	
	
M	 .	 
-21	 .	 
	 1	 	 1	 "	 1	
"		.		3	
 

21"8	9'04#2":;  901$ ; %9.#< 
2=;9
>8+
	
 

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
12.2 Appendix 2 – MRC Dyspnoea scale 
 
@


-.	3			43#	12

?C	1			"	43#	12

?C	*		1	43#	12

12		4C)		1		

12		-	=<	)	#)
 
12		
	
+	2#.3%	-12 "" 1  4 "
#11"1 4"%  4 """
(;?;8( %%" . @": 1;?.; A '. #- 
=; >
8

 

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
12.3 Appendix 3 – Radiotherapy Planning and Delivery Guidelines 
Positioning and Immobilisation 
• 
	4	.	#2		2			-"<	.1		#2	2#.1	F		6	
	C	#22	4	.	#		
• 
5	3	-,1	"	2<	3	-	4	.	2	.*	3	3	#)		3	.		
	4	.	)*		#)		*##-	.)			-"		.1<	2#1	"	
-	"	*.		
• 
5	2	43	2	)	<	3	-	-1	.	2	.1	3			3	2	
--.			 2	3	
Localisation Imaging 
• 
21		
		
• 
=-#-		3C	4	.		--	
• 
3	=	"	3			"-	.*	3			.4	3	*	
• 
		4	.	<	#	-1	<	43		4		)		
)	#)	"	.3	2=#	*	##	#)	*			#)		
	
Target Delineation 
• 
@	Q	)1	*.	223	2#			2	"			#2			-			)	
3	 	-		-<				YN		:	5)#	+	.4;	1	3	3#	.			
3C			"			2.	@	4	.		--#-	"		-				:96$5<	
+$6<	7+;				3		-		1			
• 

	Q	@	$		-)			"	-2			
• 
	Q	-2	3	3	
		-=-#-	3		-=-#-	=3	)	.1	"#)	3	
*#	@	"-	
		
• 
	Q		S	 	--	
 
Organ at Risk Delineation 
• 
	.	+	.4	
• 
+	)#		.	"#		3			321	)1	@#2	:@;	-	
#	<	*.	%	32%66444))6
7.6
#)+2=		
	
Dose Fractionation Schedules 
• 30 Gy in 3 fractions over 5 days 
 
Physics Planning 
• 
12	>			
	)3-		-1	
• 
	)	#		3	"		#	-#	.	Z	--		
• 
3	-			#	3				2	"	3		"	""	)	"-	3	22		
#	43		43	3	-	"	C)	*)	"			)	"	"")		
2	"		2-	3	C3	"	--#	2-)	43	3		3	3	"	3			
	4	.		3		"	3	)		)	C)			3	9F	
+>	
#-	)		C	:+;		

	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	!	"	((	
 
"	
#)	"	-	#	##	
2	
		
	
3	2		4	.	#				-	.*		.4	3	=	"	
3			C		2	3			+		2	-)	3#	.	
		3				3	2			2		--./	
3G#	:)		8	 	--;		433	3			3#	.		
3	 ##	 	 #	 	 	 .3	 2	 	 	 #	 G#	 	
	
>3	=#	
	

#)<		3		C	44)<	4			3	#	"-		
3	

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2		1		3	-	2	.4	3			-	
	-#	4	.	#	+	3	*		433		#	"-	
	2<	3	2		"	#	.4	3			-		
-#	4	.	#	
#)	4	#		3	2	.4	3	
		-		-#R	"1	3	-,	#C	"	3	
2	.3	2=#	4	.	#	.1	#)	3	#.*		
=1	*			#)	31	4	.	#	"-	3	."#	"	
3	.323	#C		3	,#)#6#.*	*	:	
6#.*	;<	"4)	)		)	"	3	
#*#	##		3		.
7#)	
	
$-	#)	4		"	.3	#)			##	:#)		"	
	2	)	"	#)		=#)	3	2=-	41;<	#	
	 #)	 44<	 	 )3	 	 	 )	 :-#	 3	 @	 43	
)	#)	;	
Trachea 

#)	"	3	2=-	3	3#	.)				-	#2		3	
=	"	3			 	-	#2		3		:433*		-	#2;	
	#	"1		3	#2	2	"	3	2=-	.3	
Bronchial Tree 
3	2=-	.3		4	#	3	-	"		-	"		3	
	3	2=-	41		.3		3	"4)	41	4	.	#	
)			-	32%	3			-	"	3<	3	
<	 3	 )3	 	 "	 -	 -	 .3<	 3	 )3	 	 "	 #22	 .	
.3<	3	-#	.3#<	3	)3	-	.	.3#<	3	)#	
.3#<		3	)3		"	4	.	.3	
#)	"	3	.	
.3	4		--1		3		"		)-	."#
@		
	
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44		2		3	*#	4			-##	1	#		3	
"1	*	3	)	*	3#	.	#				-	.*		
.4	 3	 =	 "	 3	 	 5	 )3	 	 <	 3	 *	 *	 4	 .	
#<		"	"		<	3		4	.	#
23)#	
	
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-	 44)	 	 3	 	 -	 	 3	 #	 4	 "	 3	
23)#		
0		
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44)	 3	 #2	 2	 	 "	 	 3	 #2	 2	 "	 3	
2#-1	1	:				#	"	3	
;		3	#	
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3		)#3.	"-	3	*		

3	?	
	
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#	3	3	*1		#			 	-	.*		.4	3	
		

 
 

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	 !	

"	
#
	$%	&&'(' 	
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''&		+	,	%	&!	
)	! 	"	((	
 
Target Coverage, Maximum Dose, Conformity Parameters and OAR Dose Constraints 
• 
)	
*)%	+-	"	3		*	.1	( M		((M	"	3			.	)	3	M		
(M	2*1	:( JM		((L(M;		
• 
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-1;		.		43	3	@	3		G#*		2.)		22=-1	3	&
( M		:*		3	-=-#-;		
• 
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• 
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• 
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3	+		4	223		2.%		
• 
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• 
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	:		"	
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3	+	-	3	2.	*		"	3	+	3			( M	"	3		3#		
		.	!M	
	
Image Guidance for Treatment Verification and Delivery 
• 

>
	:		
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Table B: Prescription dose spillage (PDS) requirements for both lung and non-lung lesions  
PTV (cc) 
Body V100%/PTV V100% 
Target 
Tolerance 
Minor Deviation 
<20 
1.20 
<1.25 
1.25-1.40 
20-40 
1.10 
<1.20 
1.20-1.30 
>40 
1.10 
<1.15 
1.15-1.20 
 
Table C: Modified Gradient Index (MGI) requirements for lung sites 
PTV 
(cc) 
Body V50%/PTV V100% 
Body-PTVExp20 
Dmax (Gy) 
Target 
Tolerance 
Minor Deviation 
3# Tolerance$ 
<20 
7 
9 
9 – 11 
<35.1 
20-40 
5.5 
6.5 
6.5 – 7.5 
<37.8 
40-60 
5 
6 
6 – 7 
<37.8 
60-90 
4 
5 
5 – 7 
<37.8 
>90 
4 
4.5 
4.5 – 6.5 
<37.8 
Body-PTVExp20 Dmax = Maximum point dose at least 2 cm from the PTV in any direction 
$During CtE no lung plan exceeded the “Tolerance” level for Body-PTVExp20 Dmax so the “Minor 
Deviation” level has been removed 
OAR parameter 
Constraints for 3# 
Optimal 
Mandatory 
BrachialPlex
D0.5cc 
24Gy 
26Gy 
Bronchus_Prox 
D0.5cc 
30Gy 
32Gy 
Chestwall 
D0.5cc 
37Gy 
- 
D30cc 
30Gy 
- 
GreatVes 
D0.5cc 
- 
45Gy 
Heart+A_Pulm 
D0.5cc 
26Gy 
30Gy 
Lungs-GTV (or ITV) 
V20Gy 
- 
10% 
Oesophagus 
D0.5cc 
- 
25.2Gy 
Skin 
D0.5cc 
33Gy 
- 
D10cc 
30Gy 
- 
SpinalCanal 
D0.1cc 
18Gy 
21.9Gy 
D1cc 
12.3Gy 
- 
Trachea 
D0.5cc 
30Gy 
32Gy 
 

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12.4 Appendix 4 - Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
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12.5 Appendix 5 - Identification, Evaluation and Management of immune related events of clinical 
interest (irECIs) 
ECI
Grade
Action to be taken
Supportive Care 
Pneumonitis –  
 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Consider bronchoscopy and 
biopsy/BAL, ID Consult and 
frequent chest x-ray for 
monitoring. 
• 
Conduct in person 
evaluation twice a week 
• 
1-2mg/kg/day prednisone or equivalent.  
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to 10mg prednisone 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
• 
Discontinue 
pembrolizumab 
• 
Hospitalise patient  
• 
Bronchoscopy with biopsy 
and/or BAL is 
recommended. 
 
• 
methylprednisolone 125mg IV.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks 
o 
Prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours  
• 
If IV steroids do not reduce initial symptoms 
within 48-72 hours treat with additional anti-
inflammatory measures. At symptom relief 
discontinue anti-inflammatory and start 
steroid taper over 45-60 days. If symptoms 
worsen during this period refer to Section 7 
and 8. 
• 
1st episode -  May increase dosing interval by one week in subsequent cycles 
• 
2nd episode of  - Pneumonitis, permanently discontinue pembrolizumab if upon re-challenge patient develops Pneumonitis 
≥ Grade 2 
Colitis 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
 – 
 
Grade 2 
(For 
grade 
2 
diarrhoea  that 
persists > 3 days) 
• 
Report overdose and liver 
toxicity ECIs within 24 
hours 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Symptomatic treatment 
o 
Consider GI consult & 
endoscopy to rule 
out colitis 
• 
Prednisone 1-2mg/kg/day or equivalent 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to 10mg or less of 
prednisone or equivalent per days within 12 
weeks. 
• 
If symptoms worsen or persist >1 week treat 
as grade 3. 

	
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)	!(	"	((	
 
Grade 3 
 
• 
Withhold pembrolizumab 
• 
Rule out bowel 
perforation 
• 
Recommend 
gastroenterologist consult 
&biopsy with endoscopy 
 
• 
methylprednisolone 125mg IV followed by 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks.  
• 
Taper 6-8 weeks in patients with diffuse or 
severe ulceration and/or bleeding 
• 
If IV steroids do not reduce initial symptoms 
within 48-72 hours treat with additional 
anti-inflammatory measures. At symptom 
relief discontinue anti-inflammatory and 
initiate steroid taper over 45-60 days. If 
symptoms worsen during this period refer 
to Section 7 and 8. 
Grade 4 
• 
Discontinue 
pembrolizumab 
• 
Manage as per grade 3 
Endocrine – Hypo and 
hyperthyroidism 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 
2 
Hyperthyroidism  
and Grade 2- 4 
Hypothyroidism 
• 
Monitor thyroid function 
until returned to baseline. 
• 
Consider consultation with 
endocrinologist. 
• 
Pembrolizumab can 
continue while on this 
treatment. 
• 
Thyroid hormone and/or steroid 
replacement therapy. 
• 
Hyper – non-selective beta blockers for 
initial therapy  
• 
Hypo – thyroid hormone replacement 
therapy as per standard of care. 
Grade 
3 
Hyperthyroidism 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Rule out infection and 
sepsis. 
• 
IV methylprednisone 1-2mg/kg followed by 
prednisone 1-2mg/kg per day.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. Replacement 
of appropriate hormones may be required. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 
4 
Hyperthyroidism 
• 
Discontinue 
pembrolizumab 
• 
Manage as per grade 3 
Endocrine 
– 
Hypophysitis or other 
symptomatic 
endocrinopathy 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 – 4  
• 
Withhold pembrolizumab 
• 
Rule out infection and 
sepsis. 
• 
Monitor thyroid function 
until returned to baseline. 
• 
Consider pituitary gland 
imaging  
• 
Hypophysitis with clinically 
significant adrenal 
• 
Prednisone 40mg p.o. or equivalent per day. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. Replacement 
of appropriate hormones may be required. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 

	
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)	(	"	((	
 
insufficiency and 
hypotension, dehydration, 
and electrolyte 
abnormalities (such as 
hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis. 
• 
Consider endocrinologist 
consult. 
Type 
1 
Diabetes 
Mellitus and ≥ grade 
3 hyperglycaemia 
Type 1 Diabetes 
Mellitus and ≥ 
grade 
3 
hyperglycaemia 
• 
Hold pembrolizumab if 
new onset of diabetes or 
grade 3-4 hyperglycaemia 
with evidence of beta cell 
failure. 
• 
Consultation with 
endocrinologist  
• 
Consider islet cell 
antibodies and antibodies 
to GAD, IA-2 ZnT8 and 
insulin. 
• 
Insulin replacement therapy is 
recommended for Type I diabetes mellitus 
and for Grade 3-4hyperglycaemia associated 
with metabolic acidosis or ketonuria. 
• 
Evaluate patients with serum glucose and a 
metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide. 
Haematologic 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Consider Haematology 
consultation 
• 
Prednisone 1-2mg/kg daily 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 3 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Recommend Haematology 
consultation 
• 
IV methlyprednisone 125mg or Prednisone 
1-2mg/kg p.o. (or equivalent) as 
appropriate. 
• 
Permanently discontinue pembrolizumab is 
if corticosteroid dose cannot be reduced to 
prednisone 10mg or less or equivalent per 
day within 12 weeks. 
Grade 4 
• 
Discontinue 
pembrolizumab 
• 
Recommend Haematology 
consultation 
• 
IV methlyprednisone 125mg or Prednisone 
1-2mg/kg p.o. (or equivalent) as 
appropriate. 
Hepatic 
– 
Drug 
induced Liver Injury 
(DILI).  
Please 
refer 
to 
Section 6 and 7 for 
definitions of (DILI) 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Report liver toxicity ECIs 
within 24 hours, as 
detailed in Section 7.5.2. 
• 
Withhold Pembrolizumab 
if AST or ALT >3.0 to 5.0 X 
ULN and/or total bilirubin 
is >1.5to 3.0 X ULN 
• 
Monitoring Liver function 
until values return to 
baseline 
• 
0.5-1mg/kg/day methlyprednisone 125mg 
or oral equivalent. 
• 
LFT grade 1 or less initiate steroid taper for 
no less than 4 weeks. Consider prophylactic 
antibiotics and resume pembrolizumab.  
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 

	
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)*	%	$
''&		+	,	%	&!	
)	(	"	((	
 
• 
Permanently discontinue pembrolizumab 
for patients with liver mets who begin 
treatment with grade 2 elevation of AST or 
ALT and AST or ALT increase ≥50% relative 
to baseline and lasts ≥ 1 week. 
Grade 3 
• 
Report liver toxicity ECIs 
within 24 hours, as 
detailed in Section 8.5.2. 
• 
Discontinue 
pembrolizumab if AST or 
ALT > 5.0 X ULN and/or 
total bilirubin is >3.0 X 
ULN 
• 
Consider consultation and 
biopsy to establish 
aetiology  
• 
High dose IV glucocorticosteroids for 24-
48hours.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks 
o 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours. 
• 
If serum transaminase levels do not 
decrease or symptoms worsen please refer 
to Section 7 and 8. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 4 
• 
Report liver toxicity ECIs 
within 24 hours, as 
detailed in Section 8.5.2. 
• 
Discontinue 
pembrolizumab 
• 
Manage as per grade 3 
Myocarditis¶ 
¶”Ensure that other 
causes of myocarditis 
are 
adequately 
evaluated to exclude 
other aetiologies 
Grade 1 and 2 
• Withhold Pembrolizumab 
• Consider Cardiology consult 
• 
Prednisone 1 – 2 mg/kg or equivalent 
• 
Restart treatment when symptoms are 
down to grade 1 and steroid dose is 
down to 10 mg or less of prednisone or 
equivalent 1-2mg/kg daily of 
prednisone or equivalent. 
Grade 3 and 4 
• Discontinue Pembrolizumab 
permanently 
• Obtain Cardiology consult 
• 
Prednisone 1 – 2 mg/kg or equivalent 
• Permanently discontinue pembrolizumab 
Neurologic 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Consider withholding 
pembrolizumab 
• 
Consider Neurology 
consult and biopsy for 
diagnosis. 
• 
Consider 1-2mg/kg daily of prednisone as 
appropriate 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 3 and 4 
• 
Discontinue 
pembrolizumab 
• 
Obtain Neurology 
consultation  
• 
Consider biopsy for 
diagnosis. 
• 
1-2mg/kg daily of prednisone or equivalent. 
• 
If condition worsens consider IVIG or other 
immunosuppressive therapies  
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks.  
Ocular 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Evaluation by 
ophthalmologist 
recommended  
• 
Topical steroids – 1%prednisolone acetate 
suspension and iridocyclitics 
• 
Permanently discontinue IF symptoms 
persist despite treatment. 

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)	(	"	((	
 
Grade 3 
 
• 
Evaluation by 
ophthalmologist 
recommended 
• 
Withhold pembrolizumab 
& consider 
discontinuation. 
• 
1-2mg/kg of prednisone daily. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 4 
• 
Evaluation by 
ophthalmologist 
recommended 
• 
Permanently discontinue 
pembrolizumab  
Manage as per grade 3 
Renal 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Withhold Pembrolizumab 
• 
1-2mg/kg of prednisone daily. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 3 and 4 
• 
Discontinue 
Pembrolizumab 
• 
Renal consultation and 
biopsy as appropriate 
• 
1-2mg/kg of prednisone daily. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
Skin 
– 
Rash 
and 
pruritus  
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Symptomatic treatment 
• 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics 
• 
Treatment with oral steroids at PIs 
discretion 
Grade 3 
• 
Withhold Pembrolizumab 
• 
Consider dermatology 
consult & biopsy for 
diagnosis. 
• 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xdaily 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 4 
• 
Discontinue 
pembrolizumab 
• 
Dermatology consultation  
• 
Consider biopsy for 
diagnosis & clinical 
photographs 
• 
Initiate steroids starting with 1-2mg/kg 
prednisone or equivalent.. 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
Skin – Dermatitis 
exfoliative, 
erythemamulitforme, 
Stevens Johnson 
syndrome§, toxic 
epidermal 
necrolysis§.  
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Symptomatic treatment 
• 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics. Treatment with oral steroids 
at PIs discretion 
Grade 3 
• 
Withhold Pembrolizumab 
• 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xday.  

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§ If it is suspected 
that the patient has 
SJS or TEN, 
pembrolizumab 
should be withheld. 
The patient should be 
referred to a 
dermatologist for 
management. If SJS 
and TEN is 
confirmed, then 
pembrolizumab 
should be 
permanently 
discontinued.” 
 
• 
Consider dermatology 
consultation and biopsy 
for diagnosis. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is 
if dose cannot be reduced to prednisone 
10mg or less or equivalent per day within 12 
weeks. 
Grade 4 
• 
Report overdose and liver 
toxicity ECIs within 24 
hours  
• 
Permanently discontinue 
pembrolizumab 
• 
Dermatology consultation  
• 
Consider biopsy for 
diagnosis & clinical 
photographs 
• 
Initiate steroids starting with 1-2mg/kg 
prednisone or equivalent.. 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
 
Other:  
• Pericarditis 
• Pancreatitis 
• Any 
additional 
Grade 3 or higher 
event which the 
physician 
considers to be 
immune related 
 
Grade 
2 
or 
Grade 1 that do 
not 
improve 
with 
symptomatic 
treatment. 
• 
Report overdose and liver 
toxicity ECIs within 24 
hours  
• 
Withhold Pembrolizumab 
• 
Consider biopsy for 
confirmation of diagnosis. 
• 
Systemic corticosteroids may be indicated. 
• 
If so: 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 
12 weeks. Otherwise, Pembrolizumab 
treatment may be restarted and the dose 
modified as specified in the protocol 
Grade 3 
• 
Withhold Pembrolizumab 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 
12 weeks. Otherwise, pembrolizumab 
treatment may be restarted and the dose 
modified as specified in the protocol 
Grade 4 
• 
Discontinue 
pembrolizumab 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
 

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12.6 Appendix 6 – Modified Response Evaluation Criteria in Solid Tumours (mRECIST) Criteria for 
Evaluating Response in Malignant Pleural Mesothelioma  
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	 !	

"	
#
	$%	&&'(' 	
)*	%	$
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)	('	"	((	
 
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	
								

	 !	

"	
#
	$%	&&'(' 	
)*	%	$
''&		+	,	%	&!	
)	(&	"	((	
 
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