Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Royal Marsden NHS Foundation Trust

  
 
 
 
 
 
                      ERM 
 
 
Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma 
(PERM) 
 
Sponsor: 
 
Royal Marsden  
Sponsor protocol number: 
CCR 4251 
EudraCT: 
2014-004065-25 
ClinicalTrials.gov ID: 
NCT02562625 
UKCRN ID:  
 
19639 
Protocol Date: 
V4.0 dated 15-Feb-2017 
REC Reference: 
15/LO/1141 
 
 
 
PLEASE DISCARD PREVIOUS COPIES BUT RETAIN ONE COPY FOR INVESTIGATOR SITE FILE 
 
CONFIDENTIAL 
 
Property of: Royal Marsden Clinical Trials Unit (RM-CTU) 
May not be used, divulged or published without the consent of: RM-CTU 
 
 

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Table of Contents 
 
CONTACT LIST ..................................................................................................................................................... 7 
Table of revisions ............................................................................................................................................ 9 
TRIAL SUMMARY ............................................................................................................................................... 19 
STATISTICIAN SIGNATURE PAGE ............................................................................................................................ 25 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ............................................................................................................ 26 
1. 
BACKGROUND & RATIONALE .......................................................................................................... 30 
1.1. 
Background ....................................................................................................................................... 30 
1.1.1. 
Pharmaceutical and Therapeutic Background ............................................................................. 30 
1.1.2. 
Preclinical and Clinical Trial Data ................................................................................................. 31 
1.2 
Rationale ........................................................................................................................................... 31 
1.2.1 
Background .................................................................................................................................. 31 
1.2.2 
Pembrolizumab in melanoma ...................................................................................................... 31 
1.2.3 
Rationale for Dose Selection ........................................................................................................ 32 
1.2.4 
Radiotherapy in combination with PD1 axis blockade. ................................................................ 33 
2 
Study OBJECTIVEs and endpoints .................................................................................................... 34 
2.1 
Study Objectives ............................................................................................................................... 34 
2.1.1 
Primary Objectives ....................................................................................................................... 34 
2.1.2 
Secondary Objectives ................................................................................................................... 34 
2.1.3 
Exploratory Objective .................................................................................................................. 35 
2.2 
Study Endpoints ................................................................................................................................ 35 
2.2.1 
Primary Endpoint ......................................................................................................................... 35 
2.2.2 
Secondary Endpoints ................................................................................................................... 35 
2.2.3 
Exploratory Endpoints.................................................................................................................. 35 
3 
STUDY DESIGN ................................................................................................................................ 36 
3.1 
Overall Study Design ......................................................................................................................... 36 
3.2 
Treatment Regimens ........................................................................................................................ 36 
3.2.1 
Additional Safety  Evaluations ..................................................................................................... 36 
3.3 
Study Flow Chart .............................................................................................................................. 37 
3.4 
Follow Up .......................................................................................................................................... 38 
3.5 
Study Termination ............................................................................................................................ 38 
3.6 
Treatment after Study Termination ................................................................................................. 38 
4.0. 
PATIENT SELECTION AND ENROLMENT ........................................................................................... 38 
4.1. 
Screening and Enrolment ................................................................................................................. 38 
4.2. 
Registration ...................................................................................................................................... 38 
4.3. 
Randomisation.................................................................................................................................. 39 
4.4. 
Entry Criteria .................................................................................................................................... 39 
4.4.1. 
Participant Inclusion Criteria ........................................................................................................ 39 
4.4.2. 
Participant Exclusion Criteria ....................................................................................................... 41 
5.0. 
Study Plan and procedures .............................................................................................................. 42 
5.1. 
Study Schedule ................................................................................................................................. 42 
5.2. 
Administrative Procedures/Assessments ......................................................................................... 45 
5.2.1. 
Informed Consent ........................................................................................................................ 45 
5.2.2. 
Inclusion/Exclusion Criteria.......................................................................................................... 45 
5.2.3. 
Demographic Data, Medical History & Treatment History .......................................................... 46 
5.2.4. 
Prior and Concomitant Medications Review ............................................................................... 46 
5.2.5. 
Survival Status .............................................................................................................................. 46 
5.3. 
Clinical Procedures/Assessments ..................................................................................................... 46 
5.3.1. 
Adverse Event (AE) Monitoring .................................................................................................... 46 
5.3.2. 
Full Physical Exam ........................................................................................................................ 47 
5.3.3. 
Targeted Physical Exam ............................................................................................................... 47 
5.3.4. 
Vital Signs, Weight & Height ........................................................................................................ 47 

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5.3.5. 
Eastern Cooperative Oncology Group (ECOG) Performance Scale .............................................. 47 
5.3.6. 
Pregnancy Tests ........................................................................................................................... 48 
5.3.7. 
Haematology, Clinical Biochemistry, PT and aPTT, Urinalysis & T3, FT4 and TSH ....................... 48 
5.3.8. 
Tumour Imaging and Assessment of Disease .............................................................................. 49 
5.4. 
Tumour Biopsies, Archival Tissue Collection & Correlative Blood Studies ....................................... 50 
5.4.1. 
Archival Tumour tissue samples - MANDATORY .......................................................................... 50 
5.4.2. 
Diagnostic Metastatic Tumour Biopsy - MANDATORY ................................................................ 50 
5.4.3. 
Tumour Tissue Collection and Correlative Studies Blood Sampling - OPTIONAL ......................... 50 
5.4.3.1. 
Peripheral Blood Analysis .................................................................................................... 50 
5.4.3.2. 
Tumour Biopsy Samples ...................................................................................................... 50 
5.4.4. 
Chain of Custody of Biological Samples ....................................................................................... 52 
5.5. 
Total Blood Volume .......................................................................................................................... 52 
6.0. 
Study Treatment ............................................................................................................................. 52 
6.1. 
Trial Treatment ................................................................................................................................. 53 
6.2. 
Standard of Care Treatment – Radiotherapy ................................................................................... 53 
6.2.1. 
Timing of radiotherapy ................................................................................................................ 53 
6.2.2. 
Sites suitable for radiotherapy ..................................................................................................... 53 
6.2.3. 
Radiotherapy techniques ............................................................................................................. 54 
6.2.4. 
Radiotherapy Dose ....................................................................................................................... 54 
6.2.4.1. Radiotherapy Quality Assurance .................................................................................................. 54 
6.3. 
Trial Treatment - Pembrolizumab .................................................................................................... 55 
6.3.1. 
Investigational Product ................................................................................................................ 55 
6.3.2. 
Product Preparation..................................................................................................................... 56 
6.3.3. 
Storage and Handling ................................................................................................................... 56 
6.3.3.1. 
Storage ................................................................................................................................ 56 
6.3.3.2. 
Handling .............................................................................................................................. 56 
6.3.4. 
Supply, Packaging and Labelling Information .............................................................................. 57 
6.3.5. 
Returns and Reconciliation .......................................................................................................... 58 
6.3.6. 
Dose Selection.............................................................................................................................. 58 
6.3.7. 
Administration of Pembrolizumab ............................................................................................... 58 
6.3.8. 
Dose Modification ........................................................................................................................ 58 
6.3.9. 
Timing of Dose Administration .................................................................................................... 59 
6.3.10. Trial Blinding/Masking ................................................................................................................. 60 
6.4. 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................................................... 60 
6.4.1. 
Acceptable Concomitant Medications ......................................................................................... 60 
6.4.2. 
Prohibited Concomitant Medications .......................................................................................... 60 
6.5. 
Rescue Medications & Supportive Care ........................................................................................... 61 
6.5.1. 
Supportive Care Guidelines.......................................................................................................... 61 
6.5.1.1. 
Diarrhoea: ............................................................................................................................ 61 
6.5.1.2. 
Nausea/vomiting: ................................................................................................................ 62 
6.5.1.3. 
Anti-infectives: .................................................................................................................... 62 
6.5.1.4. 
Immune-related adverse events: ........................................................................................ 62 
6.5.1.5. 
Management of Infusion Reactions: ................................................................................... 62 
6.5.2. 
Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-related 
Events of Clinical Interest (irECI) .................................................................................................. 63 
6.5.3. 
Supportive Care Guidelines for Pneumonitis ............................................................................... 66 
6.6. 
Diet/Activity/Other Considerations .................................................................................................. 67 
6.6.1. 
Diet ............................................................................................................................................... 67 
6.6.2. 
Contraception .............................................................................................................................. 67 
6.6.3. 
Use in Pregnancy .......................................................................................................................... 68 
6.6.4. 
Use in Nursing Women ................................................................................................................ 68 
6.7. 
Treatment of Overdose of IMP ......................................................................................................... 69 
6.8. 
Safety Follow-Up Visit....................................................................................................................... 69 
6.9. 
Survival Follow-up ............................................................................................................................ 69 
6.10. 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study .......................... 69 

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6.10.1. Permanent Discontinuation of Trial Medication.......................................................................... 69 
6.11. 
Withdrawal from the Study .............................................................................................................. 70 
7.0. 
Pharmacovigilance .......................................................................................................................... 70 
7.1. 
Definition of an Adverse Event (AE) ................................................................................................. 70 
7.1.1. 
Disease Progression ..................................................................................................................... 71 
7.1.2. 
New Cancers ................................................................................................................................ 71 
7.1.3. 
Abnormal Laboratory Test Results ............................................................................................... 71 
7.1.4. 
Pregnancy and Lactation .............................................................................................................. 71 
7.2. 
Assessing and Recording Adverse Events ......................................................................................... 71 
7.2.1. 
Evaluating Adverse Events ........................................................................................................... 72 
7.2.1.1. 
Determining AE Severity and Grade .................................................................................... 72 
7.2.1.2. 
Determining AE Causality .................................................................................................... 73 
7.2.2. 
Reporting of Pregnancy and Lactation ......................................................................................... 73 
7.3. 
Definitions of Serious Adverse Events (SAE) .................................................................................... 74 
7.4. 
Definitions of Evidence of Clinical Interest (ECI) .............................................................................. 74 
7.5. 
Reporting of SAEs ............................................................................................................................. 76 
7.5.1. 
Events exempt from being reported as SAEs ............................................................................... 76 
7.5.2. 
Determining SAE Causality and Expectedness ............................................................................. 76 
7.6. 
Reporting of ECIs .............................................................................................................................. 77 
7.7. 
Definition of an Overdose for This Protocol and Reporting of Overdose ......................................... 77 
7.8. 
Definition of a Serious Adverse Reaction (SAR) ................................................................................ 77 
7.9. 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) .................................. 77 
7.10. 
Reporting of SUSARs ......................................................................................................................... 77 
7.11. 
Annual Reporting of Serious Adverse Events ................................................................................... 78 
7.12. 
Urgent Safety Measures ................................................................................................................... 78 
8.0. 
Statistical Analysis........................................................................................................................... 79 
8.1. 
Statistical Analysis Plan Summary .................................................................................................... 79 
8.2. 
Sample Size and Power Considerations ............................................................................................ 79 
8.3. 
Randomisation.................................................................................................................................. 79 
8.4. 
Data Analysis .................................................................................................................................... 79 
8.4.1. 
Analysis populations .................................................................................................................... 80 
8.4.2. 
Study Endpoints ........................................................................................................................... 80 
8.5. 
Planned method of analysis ............................................................................................................. 81 
8.5.1. 
Safety Review Meeting ................................................................................................................ 82 
8.6. 
Deviations from the Statistical Plan ................................................................................................. 82 
8.7. 
Early Discontinuation of the Study ................................................................................................... 82 
9.0. 
Regulatory, Ethical and Legal Issues ................................................................................................ 83 
9.1. 
Good Clinical Practice ....................................................................................................................... 83 
9.2. 
Research Ethics Committee (REC)/Regulatory Authority (RA) ......................................................... 83 
9.2.1. 
Initial Approval ............................................................................................................................. 83 
9.2.2. 
Approval of Amendments ............................................................................................................ 83 
9.2.3. 
Annual Safety Reports and End of Trial Notification ................................................................... 83 
9.3. 
Regulatory Authority Approval ......................................................................................................... 84 
9.4. 
Notifications of Serious Breaches to GCP and / or the Protocol ...................................................... 84 
9.5. 
Insurance and Liability ...................................................................................................................... 84 
9.6. 
Contact with General Practitioner (GP) ............................................................................................ 84 
9.7. 
Patient Confidentiality ...................................................................................................................... 85 
9.7.1. 
Patient Confidentiality and Data Sharing ..................................................................................... 85 
9.7.2. 
Pharmacogenetics Confidentiality ............................................................................................... 85 
9.8. 
Data collection and documentation ................................................................................................. 85 
9.9. 
End of Trial ........................................................................................................................................ 86 
10.0. 
Data and study management .......................................................................................................... 86 
10.1. 
Source Data ...................................................................................................................................... 86 
10.2. 
Language .......................................................................................................................................... 86 
10.3. 
Data Collection ................................................................................................................................. 86 

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10.4. 
Electronic Recording of Data ............................................................................................................ 87 
10.5. 
Data Management ............................................................................................................................ 87 
10.6. 
Study Management Structure .......................................................................................................... 87 
10.6.1. Delegations of Responsibilities .................................................................................................... 88 
10.6.1.1. RM-CTU ............................................................................................................................... 88 
10.6.1.2. Merck, Sharp & Dohme Corp. .............................................................................................. 88 
10.6.1.3. Participating Sites ................................................................................................................ 88 
10.7. 
Protocol compliance and amendments ............................................................................................ 89 
10.8. 
Trial Management ............................................................................................................................ 89 
10.8.1. Trial Management Group ............................................................................................................. 89 
10.8.1.1. Safety Review Meetings ...................................................................................................... 89 
10.8.2. Trial Steering Committee (TSC) .................................................................................................... 89 
10.9. 
Monitoring ........................................................................................................................................ 90 
10.10. 
Quality Control and Quality Assurance ............................................................................................ 90 
10.11. 
Clinical study report ......................................................................................................................... 90 
10.12. 
Record retention .............................................................................................................................. 91 
10.13. 
Reporting and publication ................................................................................................................ 91 
11. 
REFERENCES .................................................................................................................................... 92 
APPENDICES.................................................................................................................................................. 95 
APPENDIX 1 - ................................................................................................................................................ 95 
Common Terminology Criteria For Adverse Events V4.0 (CTCAE) .................................................................. 95 
APPENDIX 2: LENT SOMA Scales for all Anatomical Sites .................................................................................... 96 
APPENDIX 3: Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 Criteria ........................................ 97 
APPENDIX 4: Identification, evaluation and management of ECIs ...................................................................... 98 
 
 
 
 
 
 
List of Figures 
Figure 1: Study Flowchart ............................................................................................................................................ 37 
Figure 2: Blood and tumour sampling schedule. ......................................................................................................... 51 
 
 
 
 
 
List of Tables 
Table 1: Adequate Organ Laboratory Values .............................................................................................................. 40 
Table 2: Schedule of Study Assessments ..................................................................................................................... 44 
Table 3: ECOG Performance Status ............................................................................................................................. 47 
Table 5: Total Volume of blood ................................................................................................................................... 52 
Table 7: Dose modification guidelines for drug-related adverse events ..................................................................... 59 
Table 9: General Approach to Handling irAEs ............................................................................................................. 64 
Table 8: Immune related AEs considered ECIs. ............................................................................................................ 75 
 
 
 
 
 

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CONTACT LIST 
 
Chief Investigator: 
James Larkin  
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Fulham Rd 
London SW3 6JJ 
Tel: 0208 915 6666 
Fax: 0208 915 6762 
Email: James.Larkin@rmh.nhs.uk 
Sponsor: 
Julie Curtis 
R&D Manager 
Clinical R&D 
Royal Marsden NHS Foundation Trust  
Fulham Rd  
London SW3 6JJ 
 
Email: julie.curtis@rmh.nhs.uk 
 
Funder: 
Cancer Research UK  
Angel Building  
407 St John Street  
London EC1V 4AD 
  
Email: www.cruk.org  
Senior Trial Manager: 
PERM Snr. Trial Manager 
Royal Marsden Clinical Trials Unit 
Royal Marsden Hospital 
Downs Rd  
Sutton SM2 5PT 
 
Tel: 0208 915 6666 
Fax: 0208 915 6762 
Email: perm.trial@rmh.nhs.uk 
 

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PROTOCOL DEVELOPMENT TEAM 
James Larkin – Chief Investigator 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
 
James.Larkin@rmh.nhs.uk 
 
Paul Nathan – Co–chief investigator 
Consultant Medical Oncologist 
Mount Vernon Cancer Centre 
 
p.nathan@nhs.net 
Kent Yip 
Consultant in Clinical Oncology 
Ipswich Hospital NHS Trust  
 
kent.yip@nhs.net 
 
Sally Ellis  
RM-CTU Operations Manager 
Royal Marsden NHS Foundation Trust 
 
Sally.Ellis@rmh.nhs.uk 
Martin Gore  
Medical Director 
Royal Marsden NHS Foundation Trust 
 
martin.gore@rmh.nhs.uk 
 
Kevin Harrington  
Hon. Consultant Clinical Oncologist 
The Institute of Cancer Research 
 
Kevin.Harrington@icr.ac.uk 
Tim Illidge  
Professor of Targeted Therapy & Oncology 
University of Manchester 
 
Tim.Illidge@ics.manchester.ac.uk 
 
Simon Dovedi 
Research Fellow 
University of Manchester 
 
Simon.Dovedi@ics.manchester.ac.uk 
 
Paul Lorigan 
Reader in Medical Oncology  
The Christie NHS Foundation Trust 
 
Paul.Lorigan@christie.nhs.uk 
Juan Martin-Liberal 
Clinical Research Fellow 
Royal Marsden NHS Foundation Trust 
 
Juan.Martin@rmh.nhs.uk 
 
PERM Senior Trial Manager  
Biomedical Research Centre - RM-CTU 
Royal Marsden NHS Foundation Trust 
 
perm.trial@rmh.nhs.uk 
 
Ann Petruckevitch 
Lead Statistician 
Royal Marsden NHS Foundation Trust 
 
Ann.Petruckevitch@rmh.nhs.uk 
 

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Page | 9 of 102 
Table of revisions made to protocol v2.0 (dated 10Jul2015) 
Page/Section 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale for substantial 
amendment 
Page 6- 
Exclusion criteria 
- 
- 
Exact text from the main part of the protocol was copied 
here to ensure consistency throughout 
Exclusion 
Criteria-
Page 16 
- 
8. Has history of Sjogren’s Syndrome 
These patients have been excluded because these patients 
are a group of patients where radiation toxicity may be 
greater and more unpredictable.  Therefore they have been 
excluded in the event that radiation  exacerbates their 
condition 
Pages 19, 20 and 21 
- 
- 
The CI, Statistician and PI Signature Pages were moved to 
the front of the protocol from the back to ensure these 
are not overlooked. 
Section 4.2, page 23 
Registration 
Following the patient’s signature of the consent form, 
this information must be entered into the electronic 
database which will allocate a unique trial identification 
number to be used to identify the patient throughout the 
study. Once all the screening assessments have been 
completed and the data entered into the eCRFs; the 
patient will be assessed for eligibility.  If eligible, the 
patient will be randomised into a treatment group. If the 
patient is not eligible then the local investigator will 
make alternative arrangements for the treatment of the 
patient. 
Registration 
Following the patient’s signature of the consent form, this 
information must be entered into the electronic database which will 
allocate a unique trial identification number to be used to identify 
the patient throughout the study.   A copy of the consent form must 
also be faxed to the Trials office to enable source data verification 
and confirm patient’s participation in the study.    
 
NOTE: Sites must alert the trials office to confirm receipt once the 
consent form has been faxed.   
 
Once all the screening assessments have been completed and the 
data entered into the eCRFs; the patient will be assessed for 
eligibility.  If eligible, the patient will be randomised into a 
treatment group. If the patient is not eligible then the local 
investigator will make alternative arrangements for the treatment 
of the patient 
As per sponsor requirements, signed copies of consent 
forms will be sent into the trials office to safely confirm 
participation.   
- 
- 
- 
The word “patient” has been replaced by the text 
“participant” throughout the protocol as recommended 
by REC to be consistent. 
 

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Page | 10 of 102 
Page/Section 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale for substantial 
amendment 
Table 2- Schedule 
of Assessments-
page 29 
- 
- 
Optional Research Blood sample taken at Screening has 
been removed from the table as this is a duplicate of the 
sample taken at Cycle 1, Wk0 sample and is unnecessary. 
Also the radiotherapy administration timepoint has been 
re-formatted to appear much clearer to the user 
Table 
4, 
Section 
5.3.7, page 33 
- 
- 
Removal of Chloride from listing as this is not clinically 
required for this study 
Figure 2-Blood and 
tumour 
sample 
schedule-page 36 
- 
- 
Updated as per Table 2 changes including stating how 
much volume of Optional Research Blood that will be 
taken 
Table 5-Total Blood 
Volume, page 37 
- 
- 
This table has been updated with the correct total 
volume of blood that will be taken throughout the study 
talking into account the 50ml which will now be taken 
instead of 24ml 
Section 7.4, page 
57, page70 
- 
Removal of the requirement to report ECIs to MSD 
An extensive study performed by (Merck, Sharpe & 
Dohme) MSD has managed to characterise the safety 
profile of Pembrolizumab and therefore no longer 
require the reporting of ECIs to MSD in an expedited 
manner.   
These events apart from those described in current 
protocol under “Definitions of Evidence of Clinical 
Interest” section and should be reported as per AE 
guidelines.  
Section 8.3, page 63 
Randomisation 
Patients will be randomised in a 1:1 ratio to receive 
pembrolizumab alone or pembrolizumab in combination 
with radiotherapy using random permuted blocks within 
strata to take account of their LDH level at baseline and 
previous anti-CTLA4 treatment.  
 
Randomisation of enrolled patients will be stratified 
based on LDH (below or within normal range / above 
upper limit of the normal range) and previous anti-CTLA4 
treatment (yes/no). The randomisation number is a 
unique number; once assigned, it becomes the 
permanent study identifier for that patient when they 
receive their treatment 
Randomisation 
Patients will be randomised in a 1:1 ratio to receive pembrolizumab 
alone or pembrolizumab in combination with radiotherapy using 
random permuted blocks within strata to take account of their LDH 
level at baseline and previous anti-CTLA4 treatment.  
Randomisation of enrolled patients will be stratified based on the 
following parameters; 
1. 
LDH (below or within normal range / above upper limit of 
the normal range)   And  
2. 
Previous anti-CTLA4 treatment (yes/no)  
The randomisation number is a unique number.   Patients will be 
identified using the number generated by the database which will 
become their unique identifier throughout the study and in all 
future correspondence.  
 
This is to clarify that the study database will auto-
generate a trial reference number which will be used as 
the unique patient identifier throughout the study.   
 
 
 

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Page | 11 of 102 
Page/Section 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale for substantial 
amendment 
Section 8.4.1,  
page 63 
Analysis populations 
The efficacy results of the trial will be analysed on an 
intention to treat (ITT) basis. The ITT population is 
defined as all patients randomised in the study and are 
analysed as randomised for response rate, PFS and OS. 
 
The safety data will be analysed by treatment received, 
irrespective of randomisation, in patients who received 
at least one treatment dose. Patients withdrawn prior to 
the first treatment dose will be excluded 
Analysis populations 
The efficacy results of the trial will be analysed on an intention to 
treat (ITT) basis. The ITT population is defined as all patients 
randomised in the study and are analysed as randomised for 
response rate, PFS and OS. 
The safety data will be analysed by treatment received, irrespective 
of randomisation, in patients who received at least one treatment 
dose. Patients withdrawn prior to the first treatment dose will be 
excluded. 
 
In addition, after 50% of the patients have been randomised and are 
evaluable for the primary endpoint an interim analysis will be 
carried out to assess the difference between the two trial arms.  In 
the event that both arms showed a RECIST response rate of 30% 
when approximately 120 patients are evaluable then it will be 
judged unlikely that the pembrolizumab and radiotherapy arm will 
show a RECIST response rate of 50% relative to the 30% RECIST 
response rate in the pembrolizumab only arm at the end of the trial 
and the trial will be stopped. 
 
As per REC recommendations following Favourable 
Opinion, a formal interim analysis was designed into the 
study to enable safe and efficient review of any 
developing issues during the study 
Section 8.7,  
page 66 
Early Discontinuation of the Study  
No formal stopping rules are planned either for efficacy, 
futility or toxicity since this study is similar to routine 
standard of care with the addition of radiotherapy.  The 
Trial Steering Committee will monitor trial progress 
including for significant safety / toxicity issues should 
they arise 
 
Early Discontinuation of the Study  
An interim analysis will be carried out when approximately 120 
patients (50%) are evaluable for the primary endpoint, this will allow 
for the early termination of the trial should there be no difference 
between the two arms, respectively. The Trial Steering Committee 
will monitor trial progress including for significant safety / toxicity 
issues should they arise. 
 
As above 
Section 9.7.1,  
page 68 
The Principal investigator must ensure that the patient’s 
confidentiality is maintained in compliance with the UK 
Data Protection Act of 1998.  On the e-CRFs or other 
documents submitted to the RM-CTU, patients should be 
identified by their initials and a patient study number 
only.  
 
The Principal Investigator must ensure that the patient’s 
confidentiality is maintained in compliance with the UK Data 
Protection Act 1998.   In all study correspondence submitted to the 
RM-CTU (apart from signed consent forms) all participants will be 
identified by their initials and unique Trial Reference study number 
only which will be used in all e-CRFs or other documents submitted 
to the RM-CTU.  
Grammatical correction 
Appendix 
1-
Radiotherapy 
Treatment 
- 
- 
The text in this Appendix 1 which includes; Summary of 
Immune Priming Radiotherapy and Organs at Risk 
Information is subject to change at any point and has 
been removed from the protocol and placed in a 
separate document called the “Radiotherapy Planning  
and QA Guidelines Manual”.  However, some text has 
been retained and moved to Section 6.2.5 to 6.2.8 of the 
protocol. 
All other Appendix documents have been rearranged in 
number order. 

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Page | 12 of 102 
Revisions made to PIS/Consent Form v2.0 dated 23Jul15 
Page/Section 
 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale for substantial 
amendment 
- 
- 
- 
For consistency, references to “patient” has been 
replaced with “participant” throughout the document. 
Question 5,  
page 2 
Extra Tests 
Optional: Collection of a research blood sample 
(approximately 6 teaspoons /24mL) before you start 
pembrolizumab  
Text removed 
The Optional Research Blood collection at screening is 
a duplication of the sample at Cycle 1, W0 time-point 
and has therefore been removed. 
Question 5 – Step 1,  
bottom of page 2 
If you are not confirmed to be suitable to take part in the 
study, you will not be able to take part in the study. 
However, your doctor will make alternative more 
suitable arrangements for the treatment of your 
condition 
 
If you are confirmed not to be suitable to take part in the study, you 
will not be able to take part in the study. However, your doctor will 
make alternative more suitable arrangements for the treatment of 
your condition 
Grammar correction 
Question 5 - Step 2,  
page 3 
Extra tests: 
Administer 200mg of pembrolizumab by IV infusion (the 
medication will be given directly into your vein) and will 
take 30 minutes every 3 weeks. 
Administer radiotherapy of 24Gy over 3 days. This will 
only be given to participants randomised to receive 
radiotherapy and will only happen between the first and 
second dose of pembrolizumab in the first Cycle; 
 
Optional:  
Collection of up to 2 tumour biopsies before your second 
dose of pembrolizumab and after radiotherapy if you are 
receiving it; 
AND 
Collection of research blood samples (approximately 6 
teaspoons/24mL) will be done on the first 5 occasions at 
each visit where you will be given pembrolizumab. This is 
to carry out tests that will help us understand how the 
body deals with the drug and what effect it has on your 
body when it is given with radiotherapy. These samples 
will be taken at the same time as the routine samples. 
Every effort will be made to take all blood samples from a 
single needle stick. 
 
 
Extra tests: 
Administer 200mg of pembrolizumab by IV infusion (the medication 
will be given directly into your vein) and will take 30 minutes every 3 
weeks. 
 
Administer radiotherapy of 24Gy over 3 days. This will only be given 
to participants randomised to receive radiotherapy and will only 
happen between the first and second dose of pembrolizumab in the 
first Cycle; 
 
Optional:  
Collection of up to 1 tumour biopsy before your second dose of 
pembrolizumab and after radiotherapy if you are receiving it; 
 
AND 
Collections of Research Blood samples (approximately 12 
teaspoons/50mL) before you start pembrolizumab; at Cycle 1(wk0), 
Cycle 2(wk3), Cycle 3(wk6), Cycle 4(wk9) and Cycle 5(wk12)).  This is 
to carry out tests that will help us understand how the body deals 
with the drug and what effect it has on your body when it is given 
with radiotherapy. These samples will be taken at the same time as 
the routine samples. Every effort will be made to take all blood 
samples from a single needle stick. 
 
The volume of Optional Research Blood has been 
changed to ensure enough cells are available to be 
analysed. 
 
 

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Page/Section 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale 
for 
substantial 
amendment 
Question 5 – Step 1,  
top of page 5 part b 
b. Punch biopsy:  A small circle of tissue sample will be 
taken using a sharp, hollow device.  You may have this 
test under local anaesthetic.  If you do not wish to give 
us this sample it will not affect your ability to take part in 
the main study. 
 
Punch biopsy:  A small circle of tissue sample will be taken using a 
sharp, hollow device. You may have this test under local 
anaesthetic.  If you do not wish to give us this sample it will not 
affect your ability to take part in the main study. 
 
 
There is a more complex test that is part of our biomarker research 
which needs to be carried out on your samples and this test can only 
be performed by a specialised laboratory which is based in the 
United States as they are specially equipped to do so.  This means 
that we will need to send part of your samples outside of the EEA to 
the United States for further processing 
 
Question 9, page 7 
Common side effects:  
 Tiredness  
 Lack of energy  
 Rash 
 Joint pain 
 Frequent or excessive bowel movements,  
 Itchy skin,  
 Feeling sick or being sick (nausea) 
 
Rare side effects: 
 Fever 
 Headache 
 Muscle cramps 
 Shortness of breath, loss of appetite 
 Cough  
 Weight loss,  
 Pain in the back,  
 Arms or legs, 
 Red rash,  
 Swelling of the legs,  
 Flu or flu like symptoms (fever, chills, body aches, 
and feeling tired),  
 Change in your vision,  
 Abnormal liver function (leading to yellowing of the 
skin or whites of the eyes, fatigue, or leg swelling), 
feeling cold, loss of skin colour, vomiting, stomach 
pains, excessive sweating in the night, decrease in red 
blood cells (leading to tiredness or shortness of 
breath),  
 Decreased thyroid activity (leading to tiredness, weight 
gain, feeling cold easily, bowel movements occurring 
less often) 
 Increased 
thyroid 
activity 
(leading 
to 
anxiety, 
irritability, trouble sleeping, weakness, trembling, 
sweating, feeling uncomfortable in warm weather, fast 
Common side effects:  
Diarrhoea/Constipation  
 
Other possible side effects: 
 Pain in the back or abdomen, arms or legs 
 Change in your vision or Uevitis  
 Abnormal liver or pancreas 
 Other changes in the hormone system (endocrinopathies) 
 Reduction in how your kidneys are working 
 Blood-clot that may cause swelling in the arms or legs or 
shortness of breath 
 Liver inflammation (Hepatitis) 
 Type 1 diabetes and its complications 
 Reaction related to pembrolizumab infusion 
 Lung inflammation (Pneumonitis) 
Updated as per amended Investigator Brochure 
(v10 dated 31Aug2015) 

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or uneven heartbeats, feeling tired, weight loss, and 
frequent or excessive bowel movements). 
 
Question 18,  
page 9 
When you sign the consent form, you agree to have your 
personal and medical information used as described in 
this section 
When you sign the consent form, you agree to have your personal 
and medical information used as described in this section.   This 
study will be monitored remotely from the Sponsor’s trials office 
but in order to safely track and confirm your participation in this 
study, a copy of your signed consent form will be sent to the 
Sponsor for their records. This document will be kept confidential 
and store securely in a locked cupboard and will only be accessible 
to authorised personnel associated with this study.  
In addition to this, a copy of your anonymised images will be sent 
electronic via a secure network outside of your local hospital for 
Central Radiology Review by the Radiotherapy Quality Assurance 
team in the UK. 
Sponsor requirements request that copies of consent 
forms sent to the trials office for verification and 
confirmation of study participation 
Consent Form   
- 
13. I give permission for a copy of this signed consent form to be 
sent to the Sponsor for their records 
Added as per information above 
Consent Form 
- 
14. I give permission for a copy of my anonymised images to be sent 
via a secure electronic system to be reviewed by the Radiotherapy 
Quality Assurance team 
The images taken for this study will be centrally 
reviewed by the Radiotherapy Quality Assurance team 
to assure consistency and uniform detection. 
Consent Form 
- 
15. I agree that part of my tissue samples will be sent outside of the 
EEA to the United States for further analysis 
Part of the tissue biopsy samples will be sent to a US 
based company who will perform specific tests (PD-L1 
testing) on each sample.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Revisions made to protocol v3.0 (dated 21Dec2015) 
 
Page/Section 
 
Previous Wording 
New Wording (tracked) 
Comments/explanation/rationale for substantial 
amendment 
Exploratory 
endpoints 
 Peripheral blood analysis (in selected sites) 
 
Absolute lymphocyte counts (ALC) to be measured 
by flow cytometry, lactate  dehydrogenase (LDH) and 
c-reactive protein (CRP) to be assayed from plasma. 
 
Peripheral 
blood 
mononuclear 
cell 
phenotype 
markers e.g. CD3, CD4, CD8, PD-1, ICOS and 
EOMES. 
 
Evaluation of HMGB1 release by mass spectrometry 
(serum). 
 
HLA-typing to permit analysis in HLA-defined 
patients (i.e. HLA-A201) of frequency of T cells 
specific for defined tumour associated antigens e.g 
NY-ESO-1. 
 
Tumour Biopsy samples (in selected sites) 
 
Immunohistochemical (IHC) analysis of tumour 
infiltrating 
immune 
cell 
populations 
and 
microenvironment e.g. CD8, CD4, FOXP3, PD-1, 
Granzyme B, PD-L1. Analysis will also include 
evaluation of TIL infiltration pattern (in relation to 
tissue architecture).  
 Optional expansion to permit isolation of DNA and 
RNA from tumour biopsy (non-laser capture) for 
expression analysis. 
 
 Peripheral blood analysis (in selected sites) 
 
Absolute lymphocyte counts (ALC) to be measured by flow 
cytometry, lactate  dehydrogenase (LDH) and c-reactive protein 
(CRP) to be assayed from plasma. 
 
Peripheral blood mononuclear cell phenotype markers e.g. CD3, 
CD4, CD8, PD-1, ICOS and EOMES. 
 
Evaluation of HMGB1 release by mass spectrometry (serum). 
 
HLA-typing to permit analysis in HLA-defined patients (i.e. 
HLA-A201) of frequency of T cells specific for defined tumour 
associated antigens e.g NY-ESO-1. 
 
Peripheral blood collected from patients at baseline, during and 
follow-up of treatment will be analysed to assess immune function in 
response to pembrolizumab ± radiotherapy.  Assays to examine 
innate and/or adaptive immune functional response may include, for 
example, immunophenotyping, cytokine/chemokine arrays.  For 
details, refer to the associated Trial Manual. 
 
Tumour Biopsy samples (in selected sites) 
 
Immunohistochemical (IHC) analysis of tumour infiltrating 
immune cell populations and microenvironment e.g. CD8, CD4, 
FOXP3, PD-1, Granzyme B, PD-L1. Analysis will also include 
evaluation of TIL infiltration pattern (in relation to tissue 
architecture).  
 
Optional expansion to permit isolation of DNA and RNA from 
tumour biopsy (non-laser capture) for expression analysis. 
 
Tumour biopsy tissue collected from patients at baseline & during 
treatment will be examined to assess the tumour microenvironment 
in response to therapy.    Tumour may be used in, for example, multi-
colour immunohistochemistry and RNA sequence analysis to 
investigate TIL infiltration & expression of known tumour-associated 
antigens.  For details, refer to the associated Trial Manual. 
 
The section is revised across the protocol for minor 
clarification.  
Table 1: Schedule 
of Study 
g8. A follow-up OPTIONAL Research Blood Sample can be taken at 
either time of response or progression (to be determined by treating 
Clarification for additional blood sample can be taken at 
either time of response or progression.  

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Assessments 
 
clinician) 
5.4.3.1 Peripheral 
Blood Analysis  
 
Consenting participants will be asked to provide an 
additional 50ml of blood at each visits prior to the 
administration of pembrolizumab for the first 12 weeks of 
treatment. Detailed processing procedures will be 
provided in a separate laboratory manual. These 
additional research bloods are considered to be research 
samples and will be retained under the University of 
Leeds Tissue Bank. All samples will undergo the 
following analysis: 
 Peripheral blood mononuclear cell phenotype markers 
e.g. CD3, CD4, CD8 with PD-1, ICOS, and EOMES.  
 Evaluation of HMGB1 release by mass spectrometry 
(serum). 
 HLA-typing to permit analysis (in HLA-defined 
participants i.e. HLA-A201) of frequency of T cells 
specific for defined tumour associated antigens e.g. NY-
ESO-1. 
Consenting participants will be asked to provide an additional 50ml 
of blood at each visits prior to the administration of pembrolizumab 
for the first 12 weeks of treatment. Detailed processing procedures 
will be provided in a separate laboratory manual. These additional 
research bloods are considered to be research samples and will be 
retained under the University of Leeds Tissue Bank. All samples will 
undergo the following analysis: 
 Peripheral blood mononuclear cell phenotype markers e.g. CD3, 
CD4, CD8 with PD-1, ICOS, and EOMES.  
 Evaluation of HMGB1 release by mass spectrometry (serum). 
 HLA-typing to permit analysis (in HLA-defined participants i.e. 
HLA-A201) of frequency of T cells specific for defined tumour 
associated antigens e.g. NY-ESO-1. 
 
Consenting participants will be asked to provide an additional 50ml 
of blood at each visit prior to the administration of pembrolizumab 
for the first 12 weeks of treatment and a further blood sample at 
either time of response or progression (to be determined by the 
relevant clinician). Detailed processing procedures will be provided 
in a separate laboratory Trial Manual. These additional research 
bloods are considered to be research samples and will be retained 
under the PERM Trial ethics until used for analysis or destroyed 
following completion of the trial.. All samples will be analysed to 
assess immune function in response to pembrolizumab ± 
radiotherapy.  Assays to examine innate and/or adaptive immune 
functional response may include, for example, immunophenotyping, 
cytokine/chemokine arrays.  For details, refer to the associated Trial 
Manual. 
 
 
5.4.3.2 Tumour 
Biopsy Samples  
 
For consenting participants post treatment biopsies will be 
taken at their second cycle of pembrolizumab ideally from 
the same lesion that was used to confirm metastatic 
disease at screening. If this biopsy was from a lesion that 
had been irradiated then if possible an additional biopsy 
outside the radiotherapy field should also be collected. 
Biopsies will be core or punch biopsies. Detailed 
processing, handling and shipping procedures for these 
biopsies will be provided in a separate laboratory  manual. 
These additional tissue biopsies are considered to be 
research samples and will be retained under the 
Manchester Cancer research Centre Tissue Bank.   
For consenting participants post treatment biopsies will be taken at 
their second cycle of pembrolizumab ideally from the same lesion 
that was used to confirm metastatic disease at screening. If this 
biopsy was from a lesion that had been irradiated then if possible an 
additional biopsy outside the radiotherapy field should also be 
collected. Biopsies will be core or punch biopsies. Detailed 
processing, handling and shipping procedures for these biopsies will 
be provided in a separate laboratory Trial manual. These additional 
tissue biopsies are considered to be research samples and will be 
retained under the Manchester Cancer research Centre Tissue Bank.  
Tumour biopsy tissue collected from patients at baseline & during 
treatment will be examined to assess the tumour microenvironment 
in response to therapy.    Tumour may be used in, for example, multi-
colour immunohistochemistry and RNA sequence analysis to 
 

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The following analyses are planned to be performed on 
the above samples: 
 Immunohistochemical (IHC) analysis of tumour 
infiltrating 
immune 
cell 
populations 
and 
microenvironment e.g. CD8, CD4, FOXP3, PD-1, 
Granzyme B, PD-L1. Analysis will also include 
evaluation of TIL infiltration pattern (in relation to 
tissue architecture).  
 Optional expansion to permit isolation of DNA and 
RNA from tumour biopsy for expression analysis 
 
investigate TIL infiltration & expression of known tumour-associated 
antigens.  For details, refer to the associated Trial Manual. 
The following analyses are planned to be performed on the above 
samples: 
 Immunohistochemical (IHC) analysis of tumour infiltrating 
immune cell populations and microenvironment e.g. CD8, CD4, 
FOXP3, PD-1, Granzyme B, PD-L1. Analysis will also include 
evaluation of TIL infiltration pattern (in relation to tissue 
architecture).  
 Optional expansion to permit isolation of DNA and RNA from 
tumour biopsy for expression analysis 
 
6.2.3. 
Radiotherapy 
Techniques 
 
As the radiotherapy fractionation schedule employed for this trial, 
24Gy/3# is not a recognised palliative dose for melanoma at present, 
and giving it concurrently with Pembrolizumab is not the standard of 
care, maintaining the safety of patients recruited into the study 
should be our absolute priority. Therefore only CtE SABR centres 
with established clinical experience in irradiating sites close to 
critical organs at risk (such as mediastinal lymph nodes, thoracic 
oligometastases, hepatic metastases and paravertebral soft tissue 
metastases) in their routine clinical practice should irradiate these 
targets in this trial. Patient recruited at sites which are non-SARB 
CtE centres, patients will still receive pembrolizumab locally at the 
site but may be irradiated at other CtE centre.  
It is anticipated that for centres with limited experience in delivering 
SABR, cutaneous metastases or superficial lymph nodes would be 
the most common targets for radiotherapy in this study. 
 
Clarification that for the PERM patient recruited at sites 
which are non-SARB CtE centres, patients will still 
receive pembrolizumab locally at the site but may be 
irradiated at other CtE centre.  
 
Figure 1: Blood 
and tumour 
sampling schedule. 
 
NA 
NA 
Figure 2 is updated for additional blood sample that can 
be taken at either time of response or progression. 
 
Table of revisions made to PIS v3.0 (dated 29Dec2015) 

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What will happen to me if 
I take part?  
 
Collections of Research Blood samples (approximately 12 
teaspoons/50mL) before you start pembrolizumab; at Cycle 1(wk0), 
Cycle 2(wk3), Cycle 3(wk6), Cycle 4(wk9) and Cycle 5(wk12) plus 
an additional sample taken at time of response or progression (to be 
determined by treating clinician).   
Clarification for additional blood sample can be 
taken at either time of response or progression.  
 
 
Take photographs of any skin lesions you may have 
Take photographs of any skin lesions you may 
have (only if done routinely at your hospital)   
 

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TRIAL SUMMARY 
 
Title 
Randomized Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma 
(PERM) 
Trial Phase 
II 
Clinical Indication 
Advanced Melanoma 
Trial Type 
Randomised 
Type of control 
Pembrolizumab alone 
Route of 
administration 
Intravenous and external radiotherapy  
Trial Blinding 
None 
Treatment Groups  
2 
Number of trial 
patients / Sites 
234 patients / 15-24 UK investigational sites 
Estimated duration 
of trial 
4 Years 
Duration of 
Participation 
Until progression or intolerance 
Study Objectives 
Primary Objective 
 To evaluate if radiotherapy will enhance the efficacy of pembrolizumab in the 
treatment of patients with metastatic melanoma by induction of an abscopal 
effect. 
Secondary Objective 
 To evaluate response rates by RECIST v1.1 post treatment 
 To evaluate response in non-irradiated lesions 
 To assess the efficacy of pembrolizumab based on Progression Free Survival 
(PFS). 
 To assess the efficacy of pembrolizumab based on Overall Survival (OS). 
 To assess the safety and tolerability of pembrolizumab alone and in 
combination with high dose radiotherapy. 
Exploratory Objective 
 Identification of biomarkers that correlate with immunological response to 
therapy 
Study Endpoints 
Primary Endpoint 
 Improvement in tumour response rate (RR) measured by RECIST 1.1 after 12 
weeks of treatment of pembrolizumab alone or with radiotherapy. 
 
Secondary Endpoints 
 Determine response rates by RECIST v1.1 at 6 months post treatment  
 To measure individual lesion response assessment every 12 weeks taking 

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account of within patient data. 
 To assess the toxicity of the combination of pembrolizumab and high dose 
radiotherapy after 12 weeks of treatment. 
 To assess PFS at 1, 2 and 3 years post treatment. 
 To assess OS in the arms of the study. 
 
Exploratory Endpoints 
A. Peripheral blood analysis (in selected sites) 
Peripheral blood collected from patients at baseline, during and follow-up of 
treatment will be analysed to assess immune function in response to 
pembrolizumab ± radiotherapy.  Assays to examine innate and/or adaptive 
immune functional response may include, for example, immunophenotyping, 
cytokine/chemokine arrays.  For details, refer to the associated Trial Manual. 
 
B. Tumour Biopsy samples (in selected sites) 
Tumour biopsy tissue collected from patients at baseline & during treatment will 
be examined to assess the tumour microenvironment in response to therapy.  
Tumour may be used in, for example, multi-colour immunohistochemistry and 
RNA sequence analysis to investigate TIL infiltration & expression of known 
tumour-associated antigens.  For details, refer to the associated Trial Manual. 
Summary of Main 
Inclusion Criteria 
1. Be willing and able to provide written informed consent for the trial. 
2. Have a diagnosis of stage III (unresectable) or stage IV cutaneous melanoma 
or melanoma of unknown primary, as per AJCC staging system. 
3. Confirmed metastatic disease by diagnostic biopsy. 
4. Be  18 years of age on day of signing informed consent. 
5. Have at least one lesion and a maximum of 3 which are appropriate targets 
for high dose radiotherapy. This lesion must be 1cm-5cm in size and 
measurable by RECIST v1.1. The lesions should also be asymptomatic or, in 
the opinion of the investigator, threaten to become symptomatic.   
6. Have in addition at least one other lesion which will not be irradiated but 
must be measurable by RECIST v1.1 to assess the abscopal effect of the 
treatment. 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1. All screening 
labs should be performed within 7 days of randomisation. 
9. Female patient of childbearing potential should have a negative urine or 
serum pregnancy test within 72 hours prior to randomisation.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.   
10. Female patients of childbearing potential should be willing to use 2 methods 
of birth control or be surgically sterile, or abstain from heterosexual activity 
for the course of the study through 120 days after the last dose of study 
medication. Patients of childbearing potential are those who have not been 

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surgically sterilized or have not been free from menses for > 1 year.  
11. Male patients should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the last 
dose of study therapy. 
Summary of Main 
Exclusion Criteria 
1. 
Has lesions that if irradiated would result in unacceptable radiation induced 
toxicity to normal tissue, in particular to the CNS and bowel  
2. 
Requires palliative radiotherapy for symptom control 
3. 
Is currently participating in or has participated in a study of an 
investigational agent or device within 4 weeks of the first dose of trial 
treatment. 
4. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to the 
first dose of trial treatment. 
5. 
Has had a monoclonal antibody within 4 weeks prior to the first dose of trial 
treatment or who has not recovered (i.e. ≤ Grade 1 or at baseline) from 
adverse events due to agents administered more than 4 weeks earlier.  
6. 
Has had chemotherapy, targeted small molecule therapy, or radiation 
therapy within 4 weeks prior to the first dose of trial treatment or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. 
Note:  participants with an AE ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
Note: if participant received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy.   
7. 
Has history of severe colitis related to previous immunotherapy treatment 
8. 
Has a past or current history of SjÖgrens Syndrome. 
9. 
Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ cervical cancer that has undergone 
potentially curative therapy.   
10. Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Participants with previously treated brain 
metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
11. Has an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune 
disease, 
or 
a 
syndrome 
that 
requires 
systemic 
steroids 
or 
immunosuppressive agents.  Participants with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule.  Participants that require 

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intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study.  Participants with hypothyroidism stable on 
hormone replacement will not be excluded from the study. 
12. Has evidence of interstitial lung disease or active, non-infectious 
pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
participant’s participation for the full duration of the trial, or is not in the 
best interest of the participant to participate, in the opinion of the treating 
investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening or 
screening visit through 120 days after the last dose of trial treatment. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137. 
18. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 
antibodies). 
19. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
20. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment 
Treatment / Main 
Study Procedures 
Patients will be randomised to receive pembrolizumab 3 weekly either alone or in 
combination with a course of high dose radiotherapy. Clinical assessments will be 
undertaken every 3 weeks on the day on which the drug is administered. Patients 
will continue on this regimen until disease progression, unacceptable toxicities, 
discontinuation of study medication or withdrawal. Patients in the radiotherapy 
arm will receive 24Gy in 3 fractions over a course of 3 consecutive days between 
the first and second doses of pembrolizumab. Patients will also undergo tumour 
assessment by RECIST 1.1 every 12 weeks from the first dose of pembrolizumab 
(irrespective of delays in treatment) to establish disease response. 
 
Please note:  
 
The 1st patient should be followed for 6 weeks or until the resolution of local 
acute toxicity to grade 1 before the second patient can begin treatment. 
 
The first 3 patients randomised to receive both pembrolizumab and 

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radiotherapy will be seen weekly for the first 6 weeks of treatment to assess 
for any grade 3 or grade 4 toxicity. If no toxicity is seen the remaining patients 
in this arm will be seen as described above. If toxicity is seen an additional 3 
patients from this arm should been seen weekly for the first 6 weeks.   
OPTIONAL: Patients in selected sites will be asked to consent to the collection of 
tumour biopsies and research bloods for translational endpoints. If a patient 
consents they will be agreeing to give both post treatment tumour biopsies and 
research blood samples. Tumour biopsies will be taken at their second cycle of 
pembrolizumab ideally from the same lesion that was used to confirm metastatic 
disease at screening. If this biopsy was from a lesion that had been irradiated 
then if possible an additional biopsy outside the radiotherapy field should also be 
collected. Biopsies will be core or punch biopsies. 24mls of research blood will be 
taken at day 1 of the first 5 cycles of pembrolizumab plus an additional sample at 
either time of response or progression (to be determined by treating clinician).  
 
 
 

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CHIEF INVESTIGATOR AND SPONSOR SIGNATURE PAGE 
Study Title: Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma 
(PERM) 
Sponsor Protocol Number:   CCR4251 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor. 
 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this protocol 
will be explained. 
 
Name of Chief Investigator:  
James Larkin 
 
Title:   
 
 
Dr 
 
Signed:  
 
Date: 14Jan2016 
 
 
 
 
 
 

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STATISTICIAN SIGNATURE PAGE 
 
Study Title: Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma 
(PERM) 
Sponsor Protocol Number: CCR4251 
 
The signature below constitutes approval of this protocol by the signatory and provides the necessary 
assurances that this study will be conducted according to EMEA ICH Topic E9 ‘Statistical Principles for 
Clinical Trials’ and the relevant standard operating procedures and policies used by RMH. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Study Title: Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma 
(PERM) 
Sponsor protocol number: CCR4251 
 
 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities as 
an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice (GCP) 
the Declaration of Helsinki and the applicable regulations of the relevant NHS Trusts and the trial 
protocol.  I agree to conduct the trial according to these regulations and guidelines and to appropriately 
direct and assist the staff under my control who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
Site Address: 
 
 
 
 
Name of Investigator: 
 
 
Title: 
 
 
Signed: 
 
 
Date: 
 
 
 
 
 
                                                 
1The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to 
it. 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALC 
Absolute Lymphocyte Counts  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APCs 
Antigen Presenting Cells 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
CI 
Chief Investigator  
CNS 
Central Nervous System 
CR 
Complete Response 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CTA 
Clinical Trial Authorisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
CTV 
Clinical Target Volume 
DAMPs 
Damage Associated Molecular Patterns 
DNA 
Deoxyribonucleic acid 
DVH 
Dose Volume Histograms 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Forms 
EudraCT 
European Clinical Trials Database 
FAS 
Full analysis set 
FFPE 
Formalin Fixed Paraffin Embeded  
GCP 
Good Clinical Practice 
GP 
General Practitioner 
GTV 
Gross Tumour Volume 
Gy 
Gray 
Hb 
Haemoglobin 
HIV 
Human Immunodeficiency Virus 
HMGB1 
High Mobility Group Box 1 
IB  
Investigator Brochure  
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonisation for Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
ICR 
Institute of Cancer Research 
ID 
Identification 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
irAE 
Immune Related Adverse Event  
irECI 
Immune Related Event of Clinical Interest  
ISF 
Investigator Site File 
ITIM 
Immunoreceptor tyrosine-based inhibition motif  
ITSM 
Immunoreceptor tyrosine-based switch motif 
ITT 
Intention to Treat 
IV 
Intravenous  
LDH 
Lactate Dehydrogenase 
LENT-SOMA 
Late Effects of Normal Tissue – Subjective, Objective, Management. 
mAb 
Monoclonal Antibody 
mg 
milligram 
MHRA 
Medicines and Healthcare Regulations Agency  
MRI 
Magnetic Resonance Imaging 
MSD 
Merck, Sharp & Dohme 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NHS 
National Health Service 
NSAIDS 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non Small Cell Lung Cancer 
OAR 
Organ At Risk 
ORR 
Overall Response Rate 
OS  
Overall Survival 
OTC 
Over the Counter 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time 
PTV  
Planning Target Volume 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
QA 
Quality Assurance 
QC 
Quality Control 
R&D 
Research and Development  
RDSU 
Research and Development Statistical Unit  
REC 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RM-CTU 
Royal Marsden Clinical Trials Unit 
RNA 
Ribonucleic acid 
RR 
Response Rate 
RT 
Radiotherapy  

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
RTTQA 
NCRI Radiotherapy Trials QA Group 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SBRT 
Stereotactic Body Radiation Therapy 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Total Triiodothyronine 
T4 
Free Tyroxine 
TILs 
Tumour-Infiltrating Lymphocytes 
TMG  
Trial Management Group 
TSC  
Trial Steering Committee 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
USM 
Urgent Safety Measure 
WBC 
White Blood Cell 
WFI  
Water for Injection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. BACKGROUND & RATIONALE 
1.1. Background 
1.1.1. Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades [1].  Accumulating evidence shows a correlation between tumour-infiltrating 
lymphocytes (TILs) in cancer tissue and favourable prognosis in various malignancies [2; 3; 4; 5; 6].  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells 
seems to correlate with improved prognosis and long-term survival in many solid tumours. The PD-1 
receptor-ligand interaction is a major pathway hijacked by tumours to suppress immune control.  The 
normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to 
down-modulate unwanted or excessive immune responses, including autoimmune reactions.  PD-1 
(encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been 
shown to negatively regulate antigen receptor signalling upon engagement of its ligands (PD-L1 and/or 
PD-L2) [7; 8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand 
binding and a cytoplasmic tail which is responsible for the binding of signalling molecules.   
 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signalling motifs, an immunoreceptor tyrosine-
based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signalling cascade [7; 10; 11; 12].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signalling proteins [13; 14].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [15; 16].  
Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as 
well as subsets of macrophages and dendritic cells [17].  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumours [18; 19; 20; 13].  Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signalling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 

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antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues [13].  Although healthy organs express little (if any) PD-
L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumour-specific T-cell expansion in patients with melanoma [21].  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumour immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as MK-3475 or SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
 
1.1.2. Preclinical and Clinical Trial Data 
Refer to the current Investigator’s Brochure for Preclinical and Clinical data. 
 
1.2 
Rationale 
1.2.1 
Background 
Around 13,000 patients are diagnosed with melanoma in the UK each year; the incidence of this disease 
is increasing more rapidly than any other type of cancer [22]. About 20% of all patients will experience 
metastatic relapse following primary treatment, and prognosis is poor with a median survival ranging 
from 9-12 months [23].  
 
In recent years, the development of new effective drugs has revolutionized the treatment of advanced 
melanoma [24]. However, the response rates are still low and novel therapeutic strategies are needed. 
The aim of this study is to confirm whether the combination of radiotherapy and the 
immunotherapeutic agent pembrolizumab can increase immune responses at distant sites in advanced 
melanoma.  
 
1.2.2 
Pembrolizumab in melanoma 
Clinical data from 135 patients with advanced melanoma treated with pembrolizumab have recently 
become available [25]. Confirmed response rate evaluated by central radiologic review according to the  
RECIST version 1.1, was 38% (95% CI, 25 to 44). The response rate did not differ significantly between 
patients who had received prior treatment with the anti-CTLA-4 antibody ipilimumab and those who had 
not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). 

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Responses were durable in the majority of patients (median follow-up, 11 months among patients who 
had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the 
time of analysis in March 2013. The overall median PFS among the 135 patients was longer than 7 
months. Common adverse events were fatigue, rash, pruritus, and diarrhoea. The majority of the 
adverse events were low grade. 
 
Although no direct comparison has been made, efficacy results with anti-PD-1 compounds such as 
pembrolizumab in melanoma are superior to those achieved with the licensed anti CTLA-4 mAb 
ipilimumab. Thus, response rates with ipilimumab are in the order of 20% whereas with the anti-PD-1 
drugs pembrolizumab or nivolumab the response rates are around 40% [26].  
 
1.2.3 
Rationale for Dose Selection  
Available pharmacokinetic (PK) results in patients with melanoma, non-small cell lung cancer (NSCLC), 
and other solid tumour types support a lack of meaningful difference in PK exposures obtained at a 
given dose among tumour types. An open-label Phase 1 trial (PN001) [27] in melanoma patients has 
been conducted to evaluate the safety and clinical activity of single agent pembrolizumab.  The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, 
administered every 2 weeks (Q2W) in patients with advanced solid tumours.  All three dose levels were 
well tolerated and no dose-limiting toxicities were observed.  This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumour size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No maximum tolerated dose (MTD) 
has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma patients receiving pembrolizumab at 
a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed [28].  The clinical efficacy and safety data 
demonstrate a lack of clinically important differences in efficacy response or safety profile at these 
doses.  For example, in Cohort B2, advanced melanoma patients who had received prior ipilimumab 
therapy were randomised to receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall 
response rate (ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full  
analysis set (FAS)).  The proportion of patients with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was comparable between 
groups or lower in the 10 mg/kg group.   

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Available pharmacokinetic results in patients with melanoma, NSCLC, and other solid tumour types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at a given dose among 
tumour types.  Population PK analysis has been performed and has confirmed the expectation that 
intrinsic factors do not affect exposure to pembrolizumab to a clinically meaningful extent.  Taken 
together, these data support the use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid 
tumour indications.  2 mg/kg Q3W is being evaluated in NSCLC in PN001, Cohort F30 and PN010, and 
200 mg Q3W is being evaluated in head and neck cancer in PN012, which are expected to provide 
additional data supporting the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation results 
indicating that 200 mg will provide exposures that are reasonably consistent with those obtained with 2 
mg/kg dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  A population PK model, which 
characterized the influence of body weight and other patient covariates on exposure, has been 
developed using available data from 476 patients from PN001.   The distribution of exposures from the 
200 mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with 
some tendency for individual values to range slightly higher with the 200 mg fixed dose.   The slight 
increase in PK variability predicted for the fixed dose relative to weight-based dosing is not expected to 
be clinically important given that the range of individual exposures is well contained within the range of 
exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  The 
population PK evaluation revealed that there was no significant impact of tumour burden on exposure. 
In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are 
no anticipated changes in exposure between different tumour types and indication settings.  
1.2.4 
Radiotherapy in combination with PD1 axis blockade. 
In addition to its well documented cytoreductive effect preclinical evidence demonstrates that 
treatment with RT can lead to the generation of a CD8+ T lymphocyte response that has the capacity to 
mediate tumour cell kill [28; 29]. Treatment with radiotherapy can lead to expression of ecto-calreticulin  
on tumour cells as well as the release of several damage-associated molecular patterns (DAMPs)  
including High Mobility Group Box 1 (HMGB1) and ATP which can lead to recruitment and activation of 
antigen presenting cells (APCs) and priming of tumour antigen-specific T-cell responses [30; 31; 32] the 
potential for the generation of effective anti-cancer immune responses following radiotherapy tumour 
microenvironments are typically characterised as immunosuppressive, attenuating the therapeutic 
capacity of the immune response [33]. More recently several studies have demonstrated that the 

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efficacy of radiotherapy can be enhanced by combination with immunotherapy which modulates the 
immune response to radiation-induced tumour cell death [34; 35]. 
 
Recent preclinical data in mouse models of cancer including melanoma, demonstrate that radiotherapy 
leads to an increase in PD-L1 expression on the surface of cancer cells which may limit anti-tumour 
immune activity. These data demonstrate that blockade of the PD-1 / PD-L1 axis with either anti-PD-1 or 
anti-PD-L1 monoclonal antibodies leads to the generation of durable anti-tumour CD8+ T cell responses  
which significantly improve local disease control and overall survival [36]. Recently published data 
support this finding that local radiotherapy may generate T cell responses that are limited by PD-1 
signalling [37] strongly supporting the combination strategy for the present study. Moreover, preclinical 
data demonstrate that only concurrent but not sequential blockade of the PD-1 / PD-L1 axis with respect 
to radiotherapy was effective at improving tumour control [36]; providing proof of principle for the 
proposed clinical trial design.   
The rationale for radiotherapy dose selection is specified in Appendix 1. 
 
 
2 
STUDY OBJECTIVES AND ENDPOINTS  
2.1 
Study Objectives 
2.1.1 
Primary Objectives 
Objective: To evaluate if radiotherapy will enhance the efficacy of pembrolizumab in the treatment of 
patients with metastatic melanoma by induction of an abscopal effect. 
Hypothesis: Radiotherapy can potentiate the systemic immunotherapeutic activity of pembrolizumab by 
induction of an abscopal effect in patients with advanced melanoma. 
 
2.1.2 
Secondary Objectives 
Objectives:  
 
To evaluate response rates by RECIST v1.1 post treatment 
 
To evaluate response in non-irradiated lesions 
 
To assess the efficacy of pembrolizumab based on Progression Free Survival (PFS). 
 
To assess the efficacy of pembrolizumab based on Overall Survival (OS). 
 
To assess the safety and tolerability of pembrolizumab alone and in combination with  
high dose radiotherapy. 

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Hypothesis: High dose radiotherapy results in immunogenic cell death resulting in release of antigens 
that stimulate a systemic immune response, converting the irradiated tissue into an in situ vaccine. 
 
2.1.3 
Exploratory Objective 
Objective: Identification of biomarkers that correlate with immunological response to therapy  
Hypothesis: Pembrolizumab will favourably alter the anti-tumour immune response in patients which an 
effect that may be increased with the combination of radiotherapy. 
 
2.2 
Study Endpoints  
2.2.1 
Primary Endpoint 
 
To evaluate improvement in tumour response rate (RR) measured by RECIST 1.1 after 12  
weeks of treatment (4 cycles) of pembrolizumab or pembrolizumab and high dose 
radiotherapy. 
 
2.2.2 
Secondary Endpoints 
 
To determine response rates by RECIST v1.1 at 6 months post treatment  
 
To measure individual lesion response assessment every 12 weeks taking account of  
within patient data 
 
To assess the toxicity of the combination of pembrolizumab and high dose radiotherapy  
after 12 weeks of treatment. 
 
To assess PFS at 1, 2 and 3 years post treatment. 
 
To assess OS in the arms of the study. 
 
2.2.3 
Exploratory Endpoints 
Exploratory immunological endpoints will be determined from patients consenting to both peripheral 
blood and tumour biopsy sampling at selected sites. 
A. Peripheral blood analysis 
Peripheral blood collected from patients at baseline, during and follow-up of treatment will be 
analysed to assess immune function in response to pembrolizumab ± radiotherapy.  Assays to 
examine innate and/or adaptive immune functional response may include, for example, 
immunophenotyping, cytokine/chemokine arrays.  For details, refer to the associated Trial Manual. 
B. Tumour Biopsy samples 
Tumour biopsy tissue collected from patients at baseline & during treatment will be examined to assess 
the tumour microenvironment in response to therapy.    Tumour may be used in, for example, multi-

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colour immunohistochemistry and RNA sequence analysis to investigate TIL infiltration & expression of 
known tumour-associated antigens.  For details, refer to the associated Trial Manual. 
 
 
3 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a multicentre, open label, randomised phase II study. 234 patients with advanced melanoma will 
be randomised to either pembrolizumab alone or in combination with high dose radiotherapy. 
Randomisation will be in a 1:1 ratio and stratified to take account of their baseline LDH and previous 
treatment with an anti-CTLA4 agent. Patients will continue their allocated treatment regimen until they 
progress, discontinue study medication or withdraw. The study will be performed at a number of 
investigational sites in the UK. 
 
3.2 
Treatment Regimens 
Patients will receive either 200mg of pembrolizumab 3 weekly alone or in combination with a high dose 
regimen of radiotherapy of 24Gy in 3 fractions given between the first and second doses of 
pembrolizumab. The patients will continue on 3 weekly doses of 200mg of pembrolizumab until disease 
progression, the development of unacceptable toxicities or withdrawal. 
3.2.1 
Additional Safety  Evaluations  
To ensure the safety of patients the 1st patient will be followed for 6 weeks or until the resolution of 
local acute toxicity to grade 1 before the second patient can begin treatment. 
In addition the first 3 patients randomised to receive both pembrolizumab and radiotherapy will be seen 
weekly for the first 6 weeks of treatment to assess for any grade 3 or grade 4 toxicities. If no toxicity is 
seen the remaining patients in this arm will be seen as described above. If toxicity is seen an additional 3 
patients from this arm should been seen weekly for the first 6 weeks.  

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3.3 
Study Flow Chart 
Figure 2: Study Flowchart  
* AE. & Con Med Review at:       
      Cycle 1-wk 1, 2
      Cycle 2-wk 3, 4, 5
      Cycle 3-wk 6 to 8  
      Cycle 4-wk 9 to 11 and
      Cycle 5-wk 12 to 14
Consent 
Screening Period from -28 to -1 days
● Physical Examination and Vital signs     
● Haematology & Biochemistry
                     ● Imaging Assessment
● Medical, Treatment, Cancer History     
● Archival Tumour  & Diagnostic metastatic Biopsy 
● AE &Con Med Review
● Demographics &ECOG
● Biopsy and blood Collection (OPTIONAL)  
                     ● Pregnancy Test
RANDOMISATION
Arm 1: Pembrolizumab Alone
Arm 2: Pembrolizumab + Radiotherapy 
Disease Progression 
Yes 
No
30 Day Safety 
Follow up*¥:
30 days after last dose 
of pembrolizumab
Survival Follow up:
After safety follow up.
Every 12 Weeks for 3 years 
Patient Off Study  
Disease Progression 
Yes 
No
200mg 
Pembrolizumab
Cycle 2*- 
Week 3-5:
3 weeks from 
day 1 cycle 1.
200mg 
Pembrolizumab
Cycle 3*- 
Week 6-8:
3 weeks from 
day 1 cycle 2.
200mg 
Pembrolizumab
Cycle 4*- 
Week 9-11:
3 weeks from 
day 1 cycle 3.
PLUS 
RADIOTHERAPY 
(24 Gy in 3 Fractions)  
12 Week RECIST Tumour 
Assessment, then at 
6mths
200mg 
Pembrolizumab
 Cycle 1*-
Week 0:
Within 3 days of 
randomisation
200mg 
Pembrolizumab
 Cycle 1¥ -
Week 0:
Within 3 days of 
randomisation
200mg 
Pembrolizumab
Every 3 weeks*¥:
Until progression, 
unacceptable toxicities 
or withdrawal
200mg 
Pembrolizumab
Cycle 2¥-
Week 3-5:
3 weeks from 
day 1 cycle 1.
200mg 
Pembrolizumab
Cycle 3¥-
Week 6-8:
3 weeks from 
day 1 cycle 2.
200mg 
Pembrolizumab
Cycle 4¥-
Week 9-11
3 weeks from 
day 1 cycle 3.
200mg 
Pembrolizumab
Cycle 5*- 
Week 12-14:
3 weeks from 
day 1 cycle 4.
200mg 
Pembrolizumab
Cycle 5¥- 
Week 12-14:
3 weeks from 
day 1 cycle 4.
Then RECIST assessments 
every 12wks post treatment
¥AE, Con Med and 
Radiology Review at;
                Cycle 1-wk 1, 2
                Cycle 2-wk 3, 4, 5
                Cycle 3-wk 6 to 8
                Cycle 4-wk 9 to 11 and
                Cycle 5-wk 12 to 14
 

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3.4 
Follow Up 
Patients will be required to attend a safety follow-up visit 30 days after the last dose of pembrolizumab 
and will be assessed for survival every 12 weeks for 3 years post treatment. Patients will not be 
expected to attend a visit for survival follow-up but information will be gathered by the research team 
from the patients’ medical notes, the patients GP and telephoning the patients directly is applicable. 
3.5 
Study Termination 
The end of the study is defined when the last patient has completed 3 years survival follow-up or has 
discontinued the study for other reasons. 
 
3.6 
Treatment after Study Termination 
Following participation in the study patient care will be decided by the local doctor according to local 
practise. 
 
4.0. 
PATIENT SELECTION AND ENROLMENT  
4.1. 
Screening and Enrolment  
Principal Investigators (PIs) should keep a record of all patients screened for entry into this study. Copies 
of the screening logs should be filed in the Site File. For each patient the primary reason for exclusion 
should be recorded. Diagnostic data obtained as part of the patient’s standard care can be used to 
determine eligibility provided they fall within the protocol defined timelines. Written informed consent 
must be obtained prior to the patient undergoing any study specific procedures. 
4.2. 
Registration 
Following the patient’s signature of the consent form, this information must be entered into the 
electronic database which will allocate a unique trial identification number to be used to identify the 
patient throughout the study.   A copy of the consent form must also be faxed to the Trials office to 
enable source data verification and confirm patient’s participation in the study.    
NOTE: Sites must alert the trials office to confirm receipt once the consent form has been faxed.   
Once all the screening assessments have been completed and the data entered into the eCRFs; the 
patient will be assessed for eligibility.  If eligible, the patient will be randomised into a treatment group. 
If the patient is not eligible then the local investigator will make alternative arrangements for the 
treatment of the patient. 

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4.3. 
Randomisation  
Patients will be randomised to receive pembrolizumab alone or in combination with radiotherapy.  
Randomisation will be performed on a 1:1 ratio basis and will be stratified based on the results of; 
1. LDH (below or within normal range/above upper limit of the normal range) and  
2. previous treatment with anti-CTLA4 agent (yes/no) 
Each site will be required to complete all screening eCRFs prior to randomisation to ensure that the 
eligibility of the patient may be confirmed.  Further information regarding randomisation procedures 
will be provided to sites in the study specific registration and randomisation SOP. 
The patients’ trial ID will be a unique that once assigned will become the permanent study identifier for 
that patient. In the event a patient is randomised onto the study but does not begin treatment, then 
that patient’s trial ID will not be reassigned. Treatment will begin within 3 days from the date of 
randomisation.  To ensure participant confidentiality, participants will only be identified by their 
assigned trial ID on eCRFs as well as on other trial specific forms and all communication to RM-CTU.  It is 
the PI’s responsibility to maintain a confidential record of the identity i.e. full name, date of birth and 
hospital number for the participants enrolled in this study and their assigned trial ID. At the end of the 
study this record should be archived along with the Site File. 
 
PLEASE NOTE: To ensure participant safety, the first participant will be followed for 6 weeks or until the 
resolution of local acute toxicity to grade 1 before the second participant may commence treatment. 
 
4.4. 
Entry Criteria 
4.4.1. Participant Inclusion Criteria 
In order to be eligible for participation in this trial, the participant must: 
1. 
Be willing and able to provide written informed consent for the trial. 
2. 
Have a diagnosis of stage III (unresectable) or stage IV cutaneous melanoma or melanoma of 
unknown primary, as per AJCC staging system. 
3. 
Confirmed metastatic disease by diagnostic biopsy. 
4. 
Be  18 years of age on day of signing informed consent. 
5. 
Have at least one lesion and a maximum of 3 which are appropriate targets for high dose 
radiotherapy. This lesion must be 1cm-5cm in size and measurable by RECIST v1.1. The lesions 
should also be asymptomatic or, in the opinion of the investigator, threaten to become 
symptomatic.   

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6. 
Have in addition at least one other lesion which will not be irradiated but must be measurable by 
RECIST v1.1 to assess the abscopal effect of the treatment. 
7. 
Have a performance status of 0 or 1 on the ECOG performance scale. 
8. 
Demonstrate adequate organ function as defined in table 1 below. All screening labs should be 
performed within 7 days of randomisation.   
System 
Laboratory Value 
Haematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥ 5.6 mmol/L  
Renal 
Serum creatinine           OR 
Measured or calculateda creatinine clearance  
(GFR can also be used in place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for participant with creatinine levels > 1.5 X 
institutional ULN 
aCreatinine clearance should be calculated per institutional standard. 
Hepatic 
Serum total bilirubin      OR 
Direct bilirubin 
≤ 1.5 X ULN OR  
≤ ULN for participants with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for participants with liver metastases 
Coagulation 
Prothrombin Time (PT) 
 
≤1.5 X ULN unless participant is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless participant is receiving anticoagulant therapy as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
Table 2: Adequate Organ Laboratory Values 
 
9. 
Female participant of childbearing potential should have a negative urine or serum pregnancy test 
within 72 hours prior to randomisation.  If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.   
10. Female participants of childbearing potential should be willing to use 2 methods of birth control or 
be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 
days after the last dose of study medication. Participants of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for > 1 year.  
11. Male participants should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
 
 

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4.4.2. Participant Exclusion Criteria 
The participant must be excluded from participating in the trial if the participant: 
1. 
Has lesions that if irradiated would result in unacceptable radiation induced toxicity to normal 
tissue, in particular to the CNS and bowel  
2. 
Requires palliative radiotherapy for symptom control 
3. 
Is currently participating in or has participated in a study of an investigational agent or device 
within 4 weeks of the first dose of trial treatment. 
4. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
5. 
Has had a monoclonal antibody within 4 weeks prior to the first dose of trial treatment or who has 
not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more 
than 4 weeks earlier.  
6. 
Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior 
to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
Note:  participants with an AE ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
Note: if participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
7. 
Has history of severe colitis related to previous immunotherapy treatment. 
8. 
Has a past or present history of Sjogren’s Syndrome 
9. 
Has a known additional malignancy that is progressing or requires active treatment.  Exceptions 
include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical 
cancer that has undergone potentially curative therapy.   
10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Participants with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.   
11. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents.  Participants with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule.  Participants that require intermittent use of 

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bronchodilators or local steroid injections would not be excluded from the study.  Participants with 
hypothyroidism stable on hormone replacement will not be excluded from the study. 
12. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the participant’s participation for the full duration 
of the trial, or is not in the best interest of the participant to participate, in the opinion of the 
treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after the 
last dose of trial treatment. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137. 
18. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
19. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
20. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
 
5.0. 
STUDY PLAN AND PROCEDURES 
5.1. 
Study Schedule  
Whilst on treatment participants will be reviewed every 3 weeks until disease progression, 
discontinuation of the study medication or withdrawal from the trial. When participants permanently 
discontinue pembrolizumab they will be required to attend a safety visit 30 days after their last dose. If a 
participant initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 
30 day Safety Follow-up visit must occur before the first dose of the new therapy. Upon completion of 
the safety visit the participants will then be followed up every 12 weeks for survival status.  
The schedule of study assessments (Table 2) summarises the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 

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Furthermore, additional evaluations/testing may be clinically indicated for reasons related to participant 
safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis 
C, etc.).  Such evaluations/testing will be performed in accordance with local regulations. 
 
 
 
 
 
 

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Table 3: Schedule of Study Assessments 
Trial Period: 
Screening 
Treatment Cycles – Every 3 Weeks 
1 to be repeated until participants discontinues trial treatment  
End of 
Treatment 7 
Safety 
Follow-Up 
Survival 
Follow-Up 
Treatment Cycle: 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle *1 
At 
discontinua-
tion of IMP 
30 days 
after last 
dose. 
Every 12 weeks 
from safety 
follow up, up 
to 3yrs 
Wk 
0 
Wk 
12 
Wk 
22 
Wk 
3 
Wk 
42 
Wk 
52 
Wk 6-8 
Wk 9-11 
Wk 12-14 
Visit Window (Days): 
-28 to -1 
± 3 
 
 
± 3 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
Administrative Procedures: 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic, Medical & Treatment 
History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures / Assessments: 
Full Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT and aPTT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiation Toxicity Review  
 
 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
 
Con Medication Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology & Biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour Imaging 
 
 
 
 
 
 
 
 
 
3 
 
4 
 
 
Targeted Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEMBROLIZUMAB  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RADIOTHERAPY  
 
        Over 3 days 
6 
 
 
 
 
 
 
 
 
 
 
Tumour Biopsies/Archival Tissue Collection/Correlative Studies Blood: 
Archival Tumour Collection (MANDATORY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic Metast’c Biopsy (MANDATORY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Biopsy (OPTIONAL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood Samples (OPTIONAL) 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
1  Cycles to be extended past cycle 5 for as long as applicable. 
2. First 3/6 randomised to Pembrolizumab and Radiotherapy arm only. 
3. Tumour imaging to be done every 12 weeks from the date of the 1st dose irrespective of delays in treatment cycles. Can be up to 7 days before visit to ensure results at the visit. 
4. Only if no RECIST assessment has been completed in the last 6 weeks. 
5. If the participant has been randomised to receive radiotherapy. 
6. For participants randomised to radiotherapy this should be administered between the 1st and 2nd dose of pembrolizumab  i.e. 24Gy in 3 fractions over 3 consecutive days 
7. End of treatment visit assessments are only applicable if the participant comes off treatment between cycles. 
8. A follow-up OPTIONAL Research Blood Sample can be taken at either time of response or progression (to be determined by treating clinician) 

 
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5.2. 
Administrative Procedures/Assessments 
5.2.1. Informed Consent 
It is the responsibility of the Principal Investigator/designee to provide each participant, prior to inclusion in the 
trial with full and adequate verbal and written information regarding the objective and procedures of the trial 
and the possible risks involved. At least 24 hours should be allowed for the participant to consider their 
participation into the trial. Participants must be informed about their right to withdraw from the trial at any 
time. Written participant information must be given to each participant before enrolment. The written 
participant information is an approved participant information sheet (PIS) according to national guidelines.  
 
The Investigator must obtain documented consent from each potential participant prior to participating in a 
clinical trial. Consent must be documented by the participant by signing and dating the consent form along 
with the dated signature of the person delivering the consent discussion. If a translator is required to fully 
explain the trial they are also required to sign and date the consent form under the witness signature line. Only 
the Principal Investigator (PI) and those Sub-Investigator(s) delegated responsibility by the PI, having signed the 
delegation of responsibilities log, are permitted to gain informed consent from participants and sign the 
consent form.  All signatures must be obtained prior to the occurrence of any medical intervention required 
by the protocol.   
A copy of the signed and dated consent form should be given to the participant before participation in the trial. 
The original consent form should be stored in the site file with a copy also being placed in the participants’ 
medical notes. 
 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the participant must receive the REC approval/favourable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the participant’s willingness to continue participation in 
the trial.  The communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature. The informed consent will adhere to REC requirements, applicable laws and 
regulations. 
 
5.2.2. Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the 
participant qualifies for the trial.  

 
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5.2.3. Demographic Data, Medical History & Treatment History  
Demographic data collected will include date of birth and race/ethnicity. A medical history will be obtained by 
the investigator or qualified designee.  Medical history will include all active conditions, and any condition(s) 
that are considered to be clinically relevant by the Investigator.  Details regarding the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as medical history.   
In addition to the medical history the investigator or qualified designee will obtain details the participant’s 
treatment history including:  
 
-Prior and current details regarding disease status  
 
-Review all prior cancer treatments including systemic treatments, radiation and surgeries  
 
5.2.4. Prior and Concomitant Medications Review 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement. In addition they will record medication, if any, taken by the participant during the trial.  
All medications related to reportable SAEs and ECIs should be recorded as defined in Section 7. 
 
5.2.5. Survival Status 
The investigator or qualified designee will assess the participant for survival status at specified visits as defined 
in the schedule of study assessment (Table 2) The assessment will include the participant status, details of anti-
cancer treatments administered and if applicable details of participant death or details if participant has been 
lost to follow-up. 
 
5.3. 
Clinical Procedures/Assessments 
5.3.1. Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant for potential new or worsening AEs at 
specified visits as defined in the schedule of study assessments (Table 2) or more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded from randomisation until the Safety follow-up. 
(Any clinical abnormalities found between informed consent and randomisation will be documented on the 
medical history form).   AEs will be graded according to NCI CTCAE Version 4.0 and LENT SOMA radiation  
toxicity grading system (see Appendices Section).  Toxicities will be characterised in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
 
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to determine if it is 
possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE).  See Section 7  

 
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regarding the identification, evaluation and management of AEs of a potential immunological etiology.  Please 
refer to Section 7 for detailed information regarding the assessment and recording of AEs.   
 
5.3.2. Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening period. 
Clinically significant abnormal findings during this period should be recorded as medical history with the start 
date and end date if applicable. If a condition is ongoing and not currently stable the CTCAE grade should also 
be recorded on the eCRF.  
  
5.3.3. Targeted Physical Exam 
Targeted physical exams will be performed at every visit as per the schedule of study assessments (Table 2), 
the investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration 
 
5.3.4. Vital Signs, Weight & Height 
The investigator or qualified designee will take vital signs and weight measurements at screening, prior to the 
administration of each dose of trial treatment and the safety follow up as specified in the schedule of study 
assessments (Table 2). Vital signs should include temperature, pulse, weight and blood pressure.  Height will be 
measured at screening only. 
 
5.3.5. Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Table 3) at screening, prior to the administration 
of each dose of trial treatment and discontinuation of trial treatment as specified in the schedule of study 
assessments. 
 
Grade 
Description 
 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair. 
Table 4: ECOG Performance Status 

 
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5.3.6. Pregnancy Tests 
Female participants of childbearing potential should have a negative urine or serum pregnancy during 
screening and within 72 hours prior to randomisation.  If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.   
 
5.3.7. Haematology, Clinical Biochemistry, PT and aPTT, Urinalysis & T3, FT4 and TSH 
Laboratory tests will be performed at screening and every visit as defined in the schedule of study assessments 
(Table 2). Sample will be analysed by the local study site laboratory using standard methods for routine tests. 
The following variables (Table 4) will be measured: 
Haematology 
Chemistry 
Urinalysis  
Other 
Haematocrit 
Albumin 
Blood 
PT  
Haemoglobin 
Alkaline phosphatase 
Glucose 
aPTT 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total triiodothyronine (T3) 
WBC (total and 
differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
Free tyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If 
results are abnormal) 
Thyroid stimulating hormone 
(TSH) 
Absolute Neutrophil 
Count 
Uric Acid 
Urine pregnancy test 
C reactive Protein (CRP) 
 
Calcium 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine  
 
 
 
Creatinine Clearance 
 
 
Table 5: Laboratory tests 
 
Laboratory tests for screening should be performed during the screening period and within 7 days prior to the 
randomisation and any abnormal results at screening should be documented on the medical history form.  
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  Results must 
be reviewed and signed by the investigator or qualified designee and found to be acceptable before the next 
dose of trial treatment is administered.  
 
Participant treatment and overall management decisions will be based on local laboratory data. The date the 
sample was taken and result for each test must be recorded in the appropriate e-CRF. After randomisation  

 
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laboratory values that are considered to be of clinical concern must be recorded as an adverse event (AE) as 
described in Section 7.1.3. Unless explained by a clinical condition, these tests must be followed up at 
appropriate intervals until they reach a level deemed acceptable by the local PI. 
 
5.3.8. Tumour Imaging and Assessment of Disease 
Tumour response assessments will be carried out by physical examination, and tumour imaging by CT scan 
and/or MRI. CT scans are the preferred modality for measureable disease unless a participant has a clinical 
condition e.g. severe contrast allergy, or the lesions are significantly better visualized through the use of an 
MRI. Tumour response will be assessed based on RECIST v1.1. (See Appendix 4) Baseline lesions must be 
selected before the start of the treatment. Tumour assessments by CT scan or MRI must be done at 12 weeks, 
and then 12 weekly thereafter until the end of treatment, progression or withdrawal of the study for any 
cause. RECIST scans can be performed up to and including 7 days before the participant is due for their next 
visit to allow the assessment of the scan to be available at the visit. 
 
If no imaging/measurement of the lesion is completed at the requested time point, then the participant cannot 
be evaluated for progression. If only a subset of the lesions are measured, then this is also considered not 
evaluable, unless a convincing argument can be made that the contribution of the individual missing lesion(s) 
would not have changed the assigned time-point response. 
 
Progression of disease should be verified by RECIST 1.1. In cases where progression is equivocal the participant 
should be re-imaged in 6 weeks. If repeat CT scans or MRI confirm PD, then progression should be declared 
using the date of the initial scan. If repeat scans do not confirm PD, then the participant is considered not to 
have progressive disease per RECIST v1.1 and the participant will return to the original imaging schedule. 
Confirmation of response is not required in these scans. Participants are allowed to continue on treatment 
beyond progression if there is clinical benefit at investigator’s criteria. 
 
Best overall response is determined once the participant has discontinued the study medication. It is defined as 
the best response designation, as determined by the investigator, recorded between the date of randomisation 
and the date of objectively documented progression per RECIST v1.1 or the date of subsequent therapy, 
whichever occurs first. For participants without documented progression or subsequent therapy, all available 
response designations will contribute to the best overall response assessment. The participant’s best overall  
response assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions.   The duration of objective response is measured from the time 

 
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measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that PD is 
objectively documented. 
 
5.4. 
Tumour Biopsies, Archival Tissue Collection & Correlative Blood Studies 
5.4.1. Archival Tumour tissue samples - MANDATORY 
Archival tissue samples will be collected all participants that have consented and have available samples.  FFPE 
tumour blocks will be requested and where it is not possible to obtain the whole block, 10-15 slides freshly 
prepared unstained 5 micron sections may be provided instead. Archival tumour blocks will be returned to 
source at the end of the study or, upon request, earlier if required for the participant’s clinical management. 
Cut sections will be retained by the study team. These are archived samples and as such participating 
participants will not need to attend extra visits or undergo extra procedures.  
5.4.2. Diagnostic Metastatic Tumour Biopsy - MANDATORY 
All participants will be required to consent to a diagnostic metastatic tumour biopsy during screening to 
confirm the presence of metastatic disease. If the participant has already had a biopsy of a metastatic lesion 
(stage 4) there is no requirement to repeat this. In addition, participants will be also asked to consent for this 
biopsy to be used in the exploratory endpoint analysis as described in section 5.4.3.2. 
5.4.3. Tumour Tissue Collection and Correlative Studies Blood Sampling - OPTIONAL 
Exploratory immunological endpoints will be determined from peripheral bloods and from tumour biopsy 
samples. Participants will be asked to consent to both tumour biopsy and blood collection to take part in this 
exploratory research.  
5.4.3.1. 
Peripheral Blood Analysis  
Consenting participants will be asked to provide an additional 50ml of blood at each visits prior to the 
administration of pembrolizumab for the first 12 weeks of treatment and a further blood sample at either time 
of response or progression (to be determined by the relevant clinician). Detailed processing procedures will be 
provided in a separate laboratory trial manual. These additional research bloods are considered to be research 
samples and will be retained under the PERM Trial ethics until used for analysis or destroyed following 
completion of the trial. All samples will be analysed to assess immune function in response to pembrolizumab ± 
radiotherapy.  Assays to examine innate and/or adaptive immune functional response may include, for 
example, immunophenotyping, cytokine/chemokine arrays.  For details, refer to the associated Trial Manual. 
 
5.4.3.2. 
Tumour Biopsy Samples  
For consenting participants post treatment biopsies will be taken at their second cycle of pembrolizumab 
ideally from the same lesion that was used to confirm metastatic disease at screening. If this biopsy was from a 

 
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lesion that had been irradiated then if possible an additional biopsy outside the radiotherapy field should also 
be collected. Biopsies will be core or punch biopsies. Detailed processing, handling and shipping procedures for 
these biopsies will be provided in a separate laboratory trial manual. These additional tissue biopsies are 
considered to be research samples and will be retained under the Manchester Cancer research Centre.  
 
Tumour biopsy tissue collected from patients at baseline & during treatment will be examined to assess 
the tumour microenvironment in response to therapy.    Tumour may be used in, for example, multi-
colour immunohistochemistry and RNA sequence analysis to investigate TIL infiltration & expression 
of known tumour-associated antigens.  For details, refer to the associated Trial Manual. 
 
Figure 3: Blood and tumour sampling schedule. 
 

 
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5.4.4. Chain of Custody of Biological Samples  
In all cases, participants will be consented for the collection and use of their biological samples and a full chain 
of custody will be maintained for all samples throughout their lifecycle. The Investigator at each site is 
responsible for maintaining a record of full traceability of biological samples collected from participants while 
these are in storage at the site, either until shipment or disposal. Anyone with custody of the samples e.g. sub-
contracted service provider will have to keep full traceability of samples from receipt to further shipment or 
disposal (as appropriate).  
RM-CTU will keep overall oversight of the entire lifecycle through internal procedures and monitoring of study 
sites. Tissue samples retained for further use will be registered with the Manchester Cancer Research Centre 
and research blood samples retained for further use under the PERM trial ethics. 
5.5. 
Total Blood Volume 
The total volume of blood that will be drawn from each trial participant for the assessments described in the 
sections above is shown in Table 5. 
 
Sample volume (mL) 
No. of samples 
Total 
volume (mL) 
Routine Haematology 
6 
181 
108 
Routine Clinical chemistry 
8 
181 
144 
Total Routine 
252 
Peripheral Blood Sampling (Optional) 
50 
5 
250 
Total: 
5022 
Table 6: Total Volume of blood  
To be drawn from each trial participant for the duration of the trial; calculations based on 1 year on treatment, plus end of treatment 
visit and 30 days post end of treatment safety visit (where applicable). 
 
 Blood volumes for haematology and clinical chemistry may vary according to local practice 
2 The total volume of blood drawn from each trial participant for the duration of the trial depends on the time to progression for each 
participant. 
 
 
 
 
 
 
 
 
 
6.0. STUDY TREATMENT 

 
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6.1. 
Trial Treatment 
Participants will be randomised to receive either pembrolizumab alone or pembrolizumab and high dose 
radiotherapy.   Images will be reviewed centrally by the Radiotherapy Quality Assurance team to ensure 
consistency in reviewing images2.  The doses to be administered are: 
1. Pembrolizumab 200mg every 3 weeks by intravenous infusion until progression, intolerance or 
withdrawal. 
2. High dose radiotherapy, 24Gy in 3 fractions over 3 consecutive days to a deposit of melanoma after 
the first and before the second pembrolizumab infusion is given.  Radiotherapy will be targeted at one 
or more suitable lesions (maximum of 3). At least one of the lesions will be left un-irradiated and will 
serve as the index lesion for subsequent evaluation.  
 
6.2. 
Standard of Care Treatment – Radiotherapy3  
6.2.1. Timing of radiotherapy 
Radiotherapy (RT) should begin after the first and before the second dose of pembrolizumab. For participants 
due to receive RT to their internal metastases, radiotherapy planning should commence as soon as they have 
been recruited into the study to allow adequate time for prospective case reviews and feedback of 
radiotherapy plans.  
 
6.2.2. Sites suitable for radiotherapy 
Participants must have at least two sites of metastatic disease from their primary melanoma.  One of the 
metastatic sites will serve as the index lesion for subsequent assessment of the abscopal effect and should not  
receive RT. A maximum of 3 Lesion(s) can be irradiated and must be at least 1 cm but no more than 5 cm in 
size, as measured by its widest dimension on CT scan (for internal lesions) or on clinical inspection (for 
superficial lesions). Metastatic lesions must not be an intra-cranial, intra-ocular lesion or intra-mesenteric 
lesion to receive RT.  The choice of the lesion(s) to be irradiated will be left to the discretion of the attending 
oncologist, taking into account the Organs At Risk (OAR) normal tissue tolerance constraints associated with  
irradiating each lesion, and importantly the ease of obtaining pre and post radiotherapy biopsies from the 
index lesion(s) for the associated translational study. For example, if there is one internal and one superficial 
                                                 
2 Patients will be consented to allowing their images to be sent outside of their institution.   Please refer to the current Radiotherapy 
Imaging Manual for further guidance 
3 Further information on this section is available in the current Radiotherapy QA Guidelines Manual which will be provided by the trials 
office 

 
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lesion, it may be preferable to irradiate the internal lesion so that biopsy can be taken from the superficial 
lesion pre and post irradiation.  
 
6.2.3. Radiotherapy techniques 
Appropriate radiotherapy techniques should be used to ensure dose coverage of the irradiated lesions and to 
respect the organs at risk constraints as specified (see the current Radiotherapy QA Guidelines Manual for 
further information).   It is envisaged that the majority of metastases to be irradiated will be those on the skin 
and in the superficial nodes, in which case either electron or 3D conformal radiotherapy can be used.  The 
attending oncologist may choose to irradiate metastases in the liver, lung, para-vertebral region or deep seated 
nodes. In these cases complex IMRT or SBRT techniques may be appropriate and will be permitted. 
 
As the radiotherapy fractionation schedule employed for this trial, 24Gy/3# is not a recognised palliative dose 
for melanoma at present, and giving it concurrently with Pembrolizumab is not the standard of care, 
maintaining the safety of patients recruited into the study should be our absolute priority. Therefore only CtE 
SABR centres with established clinical experience in irradiating sites close to critical organs at risk (such as 
mediastinal lymph nodes, thoracic oligometastases, hepatic metastases and paravertebral soft tissue 
metastases) in their routine clinical practice should irradiate these targets in this trial. Patient recruited at sites 
which are non-SARB CtE centres, patients will still receive pembrolizumab locally at the site but may be 
irradiated at other CtE centre.  
 
It is anticipated that for centres with limited experience in delivering SABR, cutaneous metastases or superficial 
lymph nodes would be the most common targets for radiotherapy in this study. 
 
6.2.4. Radiotherapy Dose  
Lesion(s) will be irradiated to the dose of 24Gy in 3 fractions delivered over 3 consecutive days in cycle 1. 
 
6.2.4.1. Radiotherapy Quality Assurance  
The QA programme for the study will be designed and implemented by the NCRI Radiotherapy Trials QA  
(RTTQA) Group.  The programme will compose pre-trial and on-trial QA components to ensure adherence to  
protocol requirements. 
6.2.4.2. Pre-Accrual QA 
1. Facility Questionnaire 

 
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Participating centres will be asked to complete a facility questionnaire on general and trial specific questions on 
recent independent audit history, equipment, software and techniques to be used for the trial. 
 
2. Process Document 
Participating centres will be asked to submit a process document, detailing the entire radiotherapy planning 
chain for all of the radiotherapy techniques to be used by the site in this trial. 
 
3. Dummy run 
Participating centres may be asked to export a centre participant planned and treated according to the trial 
protocol.  The outlining and planning for this case will be independently reviewed in terms of protocol 
adherence. 
6.2.4.3. IMRT and SABR use for the trial 
All centres intending to use IMRT techniques must be IMRT credentialed through the RTTQA group or accepted 
equivalent.  Further information on this process is available at www.rttrialsqa.org.uk.  Those centres intending 
to use SABR techniques, to irradiate internal metastatic lesions, must have completed the UK SABR audit. 
 
6.2.4.4. On Trial Quality Assurance 
1.Plan Assessment Form: An electronic copy of the plan assessment form containing key treatment details 
must be completed and submitted for all participants.  These will be reviewed prospectively for all participants.  
2.Export of electronic data: structure sets, dose and plan data for all recruited participants to be exported to 
the RTTQA group. 
3. Prospective (real time) review:  For participants with internal metastases: all cases will be participant to 
prospective review of outlining and planning.   
4. For all other cases: prospective review of the Plan Assessment Form only. 
 
Non-compliance of outlining or planning for the trial will be highlighted to the Chief Investigator (CI) and local 
Principal Investigators (PIs) and appropriate action taken. 
 
6.3. 
Trial Treatment - Pembrolizumab  
6.3.1. Investigational Product  
The Investigational Medicinal Product (IMP) for this study is Pembrolizumab. A potent and highly-selective 
humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Pembrolizumab potentiates existing immune responses only in the presence of 
antigen and does not non-specifically activate T-cells. 

 
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Pembrolizumab will be manufactured by MSD according to Good Manufacturing Practice and will be provided 
in the formulation as described in Table 6. Additional information about the investigational product can be 
found in the current Investigator’s Brochure (IB). 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Table 7: Product Description 
 
6.3.2. Product Preparation 
The powder for infusion is a sterile, non-pyrogenic lyophilized powder for intravenous infusion supplied in 
single-use Type I glass vial containing 50mg of pembrolizumab. The product is preservative-free, white to off-
white powder and free from visible foreign matter.  
 
The powder will need to be reconstituted with 2.3 mL sterile water for injection (WFI) to yield a 2.4 mL solution 
containing 25 mg/mL of pembrolizumab at pH 5.2 – 5.8.   Each vial contains an excess fill of 10 mg (equivalent 
to 0.4 mL of reconstituted solution) to ensure the recovery of label claim of 50 mg MK-3475 per vial (equivalent 
to 2.0 mL of reconstituted solution).  
 
6.3.3. Storage and Handling 
6.3.3.1. Storage  
The original powder for infusion should be stored at refrigerated conditions (2 – 8°C). Prior to reconstitution, 
the vial can be out of refrigeration (temperatures at or below 25°C (77°F)) for up to 24 hours.  
 
Prepared infusion solutions may be stored at room temperature for a cumulative time of up to 4 hours. This 
includes room temperature storage of reconstituted drug product solution in vials, room temperature storage 
of admixture solutions in the IV bags and the duration of infusion. In addition, reconstituted vials and/or IV 
bags may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 20 hours. If refrigerated, allow the 
vials and/or IV bags to come to room temperature prior to use.  
 
6.3.3.2. Handling 
Infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal saline) or regional 
equivalent and the final concentration of pembrolizumab in the infusion solutions should be between 1.0 
mg/mL and 10.0 mg/mL.   If normal saline is not available, 5% Dextrose Injection, USP or regional equivalent 

 
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(5% dextrose) is permissible, Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is 
only permissible if normal saline is not available. 
 
Pembrolizumab should NOT be mixed with other diluents unless instructed by the sponsor in writing.  
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration. Discard the drug product vial if extraneous particulate matter other than translucent to white 
proteinaceous particles is observed.  Sites should follow their SOPs for drug transport and delivery, with all 
possible effort to minimize agitation of the reconstituted drug product between the pharmacy and the clinic. 
DO NOT: 
 Use if discoloration is observed 
 
 Shake or freeze the vial(s) 
 
 Administer the product as an (intravenous (iv) push or bolus) 
 
 Combine, dilute or administer it as an infusion with other medicinal products 
 
 Co-administer other drugs through the same infusion line 
Further details on the preparation of the drug product can be found in the IMP handling guidelines.  
At each site the Investigator / designee e.g. pharmacist is responsible for ensuring that all trial medication is 
stored in a secure, limited-access location under the storage conditions specified on the label.  Receipt and 
dispensing of trial medication must be recorded by an authorized person at the trial site. Trial medication may 
not be used for any purpose other than that stated in the protocol. 
 
6.3.4. Supply, Packaging and Labelling Information 
Pembrolizumab will be supplied by Merck, Sharp and Dohme (MSD) as lyophilized powder for injection. 
Pembrolizumab will be packaged, labelled and delivered to the participating sites by MSD. The IMP will be 
supplied specifically for the trial and should not be used for any other purpose than that stated in this protocol. 
The drug will be labelled in accordance to Good Manufacturing Practice Annex 13. As a minimum the labels will 
include the following information; 
a. name of the Sponsor 
b. name of drug, dose, quantity of dose units and route of administration 
c. batch number to identify the contents and packaging operation 
d. blank space for recording the trial ID 
e. directions for use 
f. PI name 

 
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g. protocol number 
h. storage conditions 
i. expiry date 
j. “for clinical trial use only” 
k. “keep out of reach of children” 
 
6.3.5. Returns and Reconciliation 
The Investigator/designee is responsible for keeping accurate accountability records for pembrolizumab 
including the amount dispensed to and returned for each participant and the amount remaining on site at the 
conclusion of the trial.  
 
Upon completion or termination of the study, it is the Investigators/designee responsibility to ensure all 
unused and partially used trial medication will be destroyed at the site per local guidelines and provide 
appropriate records of disposal to the sponsor with a copy being stored in the pharmacy site file. 
 
6.3.6. Dose Selection 
The rationale for selection the dose to be used in this trial is provided in Section 1.0 – Background and 
Rationale. All randomised participants will receive pembrolizumab given as 200mg every 3 weeks by 
intravenous infusion until progression, intolerance or withdrawal from the trial.  
 
6.3.7. Administration of Pembrolizumab 
Details on the preparation and administration of pembrolizumab are provided in the IMP handling guidelines. 
These guidelines contain specific instructions for pembrolizumab reconstitution, preparation of the infusion 
fluid, and administration. 
 
6.3.8. Dose Modification  
Pembrolizumab will be withheld for drug-related haematological and non-haematological of toxicity ≥ Grade 3 
including laboratory abnormalities, and severe or life-threatening AEs as per Table 7 below. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhoea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 

 
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Increased 
Bilirubin 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure. 
Resume pembrolizumab when participants are 
clinically and metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For participants with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then participants should be discontinued. 
2 Participants with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 
weeks of the last dose. 
Table 8: Dose modification guidelines for drug-related adverse events 
 
If the toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment should be 
discontinued at the discretion of the investigator. Participants with a laboratory adverse event still at Grade 2 
after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.  For information on 
the management of adverse events, see section 7.    
 
Participants who experience a recurrence of the same severe or life-threatening event at the same grade or 
greater with re-challenge of pembrolizumab should be discontinued from trial treatment. 
 
6.3.9. Timing of Dose Administration 
Pembrolizumab will be administered on an outpatient basis on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the schedule of study assessments (Table 2).  

 
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Pembrolizumab will be administered via a 0.2-5µm in-line filter as a 30 minute IV infusion (treatment cycle 
intervals or infusion length may be increased due to toxicity as described in Section 6.3.3).  Due to the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min).  In addition, infusion length may be increased due to toxicity as 
described in Section 6.3.3.  
 
6.3.10. Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the treatment being 
administered. 
6.4. 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed during the trial.  
If there is a clinical indication for one of these or other prohibited medications or vaccinations then 
discontinuation from trial therapy may be required.  The Investigator should discuss any questions regarding 
this with the CI/designee/RM-CTU.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the participant on 
trial therapy schedule requires the mutual agreement of the Investigator, CI/ designee, and the participant.  
 
6.4.1. Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be administered at the 
discretion of the investigator in keeping with the standards of medical care.  All concomitant medication will be 
recorded on the e-case report form (e-CRF) including all prescriptions, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  All concomitant medications received within 28 days before the 
first dose and until the safety follow up visit should be recorded.   
 
6.4.2. Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the screening and treatment phase 
(including retreatment for post-complete response relapse) of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Radiotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Palliative radiotherapy for symptom control 
 Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial.  

 
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Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed.  
 Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the CI/designee.  
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Participants may receive other 
medications that the investigator deems to be medically necessary. The Exclusion Criteria describes other 
medications which are prohibited in this trial. There are no prohibited therapies during the Post-Treatment 
Follow-up Phase. 
 
6.5. 
Rescue Medications & Supportive Care 
6.5.1. Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below: 
 
6.5.1.1. 
Diarrhoea:  
Participants should be carefully monitored for signs and symptoms of:  
 Enterocolitis (diarrhoea, abdominal pain, blood or mucus in stool, with or without fever)  
 Bowel perforation (peritoneal signs and ileus).   
In symptomatic participants, infectious etiologies should be ruled out, and if symptoms are persistent and/or 
severe, endoscopic evaluation should be considered. 
 In participants with severe enterocolitis (Grade 3):  
o Pembrolizumab will be permanently discontinued and treatment with systemic corticosteroids 
should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
 In participants with moderate enterocolitis (Grade 2): 
o  Pembrolizumab should be withheld and anti-diarrhoeal treatment should be started.  If 
symptoms are persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve to Grade 1 or 

 
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less, corticosteroid taper should be started and continued over at least 1 month.  Guidelines 
for continuing treatment with pembrolizumab can be found in Appendix 5. 
o All participants who experience diarrhoea should be advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted 
via IV infusion. 
 
6.5.1.2. 
Nausea/vomiting:  
Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles to 
the administration of prophylactic antiemetic therapy according to standard institutional practice.  Participants 
should be strongly encouraged to maintain liberal oral fluid intake. 
 
6.5.1.3. 
Anti-infectives:  
Participants with a documented infectious complication should receive oral or IV antibiotics or other anti-
infective agents as considered appropriate by the treating investigator for a given infectious condition, 
according to standard institutional practice. 
 
6.5.1.4. 
Immune-related adverse events:  
Please see Section 6.5.2 below regarding diagnosis and management of adverse experiences of a potential 
immunologic etiology.   
 
6.5.1.5. 
Management of Infusion Reactions:   
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or anaphylaxis) are 
different from allergic/hypersensitive reactions, although some of the manifestations are common to both AEs.  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity 
(including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); 
Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); Nausea; 
Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumour pain (onset or 
exacerbation of tumour pain due to treatment); Urticaria (hives, welts, wheals); Vomiting. 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
 
None 

 
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indicated; intervention not indicated 
the investigator. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
 IV fluids 
 Antihistamines 
 NSAIDS 
 Acetaminophen 
 Narcotics 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator. 
 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and the 
participant should be pre-medicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
 
Participant may be pre-
medicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalisation indicated for other clinical 
sequelae 
(e.g., 
renal 
impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
 IV fluids 
 Antihistamines 
 NSAIDS 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroids 
 Epinephrine 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator. Hospitalisation may be indicated. 
Participant is permanently discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration.  For 
Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
Table 8: below shows treatment guidelines for participants who experience an infusion reaction associated with administration of 
pembrolizumab. 
 
6.5.2. Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-related 
Events of Clinical Interest (irECI)  
Immune-related Adverse events (IrAEs) may be defined as an adverse event of unknown etiology, associated 
with drug exposure and is consistent with an immune phenomenon. IrAEs may be predicted based on the 

 
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nature of the pembrolizumab compound, its mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action.  Special attention should be paid to AEs that may be 
suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several months after the last dose 
of treatment.   
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes prior to labeling an adverse event as an irAE.  Participants who develop a Grade 2 or higher 
irAE should be discussed immediately with the CI/designee.   
 
Recommendations to managing irAEs not detailed elsewhere in the protocol;  
irAE 
Withhold/Discontinue pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
Grade 3 and Grade 4 
Withhold pembrolizumab 
Discontinue if unable to reduce corticosteroid dose to < 10 mg per 
day prednisone equivalent within 12 weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 2 
mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
Please Note:  
If an irAE does not resolve or improve to ≤ Grade 1 within 12 weeks after last administration of pembrolizumab, study therapy discontinuation should be 
considered after discussion with a Merck Clinical Director via the RM-CTU trial manager.. 
Table 9: General Approach to Handling irAEs 
 
Details for managing specific irAEs are summarised below: 
Immune-mediated pneumonitis 
Monitor participants for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with 
radiographic imaging. Exclude other causes of pneumonitis, and manage treatment in accordance with the 
guidelines above. Administer corticosteroids, withhold pembrolizumab for moderate (Grade 2) pneumonitis, 
and permanently discontinue pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) pneumonitis. 
 
Immune-mediated colitis 
Monitor participants for signs and symptoms of colitis. Exclude other causes of colitis, and manage treatment 
in accordance with the guidelines above. Administer corticosteroids, withhold pembrolizumab for moderate  
(Grade 2) or severe (Grade 3) colitis, and permanently discontinue pembrolizumab for life-threatening (Grade 
4) colitis. 

 
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Immune-mediated hepatitis 
Monitor participants for changes in liver function (at the start of treatment, periodically during treatment and 
as indicated based on clinical evaluation) and symptoms of hepatitis. Exclude other causes of hepatitis, and 
manage treatment in accordance with the guidelines above. Administer corticosteroids and, based on severity 
of liver enzyme elevations, withhold or discontinue pembrolizumab. 
 
Immune-mediated nephritis 
Monitor participants for changes in renal function. Exclude other causes of nephritis, and manage treatment in 
accordance with the guidelines above. Administer corticosteroids, withhold pembrolizumab for moderate 
(Grade 2), and permanently discontinue pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) 
nephrits. 
 
Immune-mediated endocrinopathies 
Monitor participants for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency). Exclude other causes of hypophysitis, and manage treatment in accordance with the guidelines 
above. Administer corticosteroids, withhold pembrolizumab for moderate (Grade 2), withhold or discontinue 
pembrolizumab for severe (Grade 3) and for life-threatening (Grade 4) hypophysitis. 
 
Monitor participants 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. 
 
Thyroid disorders have been reported in participants receiving pembrolizumab and can occur at any time 
during treatment; therefore, monitor participants for changes in thyroid function (at the start of treatment, 
periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of 
thyroid disorders. Administer corticosteroids, withhold pembrolizumab for severe (Grade 3) hyperthyroidism, 
and permanently discontinue pembrolizumab for life-threatening (Grade 4) hyperthyroidism. Treat symptoms 
of hyperthyroidism as appropriate. Isolated hypothyroidism may be managed with replacement therapy 
without treatment interruption and without corticosteroids. For participants with severe (Grade 3) or life-
threatening (Grade 4) endocrinopathy that resolved and is controlled with hormone replacement, continuation 
of pembrolizumab may be considered. 
 
 

 
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Other immune-mediated adverse events 
Across clinical studies with pembrolizumab in approximately 5000 participants, the following additional 
clinically significant, immune-mediated adverse reactions were reported in less than 1% of participants: uveitis 
and severe skin reactions. 
 
In addition a set of irAEs have also been classified as immune-related events of clinical interest (irECI) a full list 
of these can been found in events of clinical interest guidance in Section 7.4.  Participants with symptomatic 
irECIs should immediately stop receiving pembrolizumab and be evaluated to rule out non treatment related 
causes of the event.   Overdose and liver toxicity irECIs irrespective of relationship to the study drug should be 
reported within 24 hours of the investigator being aware of the event to the Sponsor who will in turn notify 
MSD. If the irECI is determined to be associated please refer to Appendix 4 for the recommendations on the 
management of these irECIs. If the event is not considered to be associated with the study drug the physician 
should exercise individual clinical judgment on the event management based on the participant.  Any 
additional questions of the collection or information on management of irECIs should be directed to the 
Sponsor. 
 
6.5.3. Supportive Care Guidelines for Pneumonitis 
Participants with symptomatic pneumonitis should immediately stop receiving pembrolizumab and have an 
evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to rule out other causes 
such as infection.  If the participant is determined to have study drug associated pneumonitis, the suggested 
treatment plan is detailed in Table 10. 
Study drug associated 
pneumonitis 
Withhold/Discontinue pembrolizumab? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab, may return to 
treatment if improves to Grade 1 or resolves 
within 12 weeks. Second episode of 
pneumonitis – discontinue pembrolizumab if 
upon re-challenge the participant develops a 
second episode of Grade 2 or higher 
pneumonitis. 
Consider pulmonary consultation with bronchoscopy 
and biopsy/BAL. 
 
Conduct an in person evaluation approximately twice 
per week 
 
Consider frequent Chest X-ray as part of monitoring 
Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent. When symptoms 
improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
Consider antibiotics 
Grade 3 and Grade 4 
Discontinue pembrolizumab 
Hospitalise participant 

 
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Bronchoscopy with biopsy and/or BAL is recommended. 
Immediately 
treat 
with 
intravenous 
steroids 
(methylprednisolone 125 mg IV). When symptoms 
improve to Grade 1 or less, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be 
started and continued over no less than 4 weeks. 
If IV steroids followed by high dose oral steroids does 
not reduce initial symptoms within 48 to 72hours, treat 
with 
additional 
anti-inflammatory 
measures. 
Discontinue additional anti-inflammatory measures 
upon symptom relief and initiate a prolonged steroid 
taper over 45 to 60 days. If symptoms worsen during 
steroid reduction, initiate a re-tapering of steroids 
starting at a higher dose of 80 or 100mg followed by a 
more prolonged taper and administer additional anti-
inflammatory measures, as needed Add prophylactic 
antibiotics for opportunistic infections. The use of 
infliximab may be indicated as appropriate. 
Table 10: Recommended Approach to Handling Pneumonitis 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
 Second episode of pneumonitis  
o Permanently discontinue pembrolizumab if upon re-challenge participant develops  
pneumonitis  Grade 2 
 
6.6. 
Diet/Activity/Other Considerations 
6.6.1. Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhoea, nausea or vomiting. 
 
6.6.2. Contraception 
Pembrolizumab may have adverse effects on a foetus in utero.  Furthermore, it is not known if pembrolizumab 
has transient adverse effects on the composition of sperm.  Non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive.  
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be either, two barrier 

 
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methods or a barrier method plus a hormonal method to prevent pregnancy. Participants should start using 
birth control from screening throughout the study period up to 120 days after the last dose of study therapy. 
Male participants with partners of child bearing potential will also be required to agree to use an adequate 
method of contraception starting with the first dose of study therapy through 120 days after the last dose of 
study therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), 
copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will include any 
registered and marketed contraceptive agent that contains an oestrogen and/or a progestational agent 
(including oral, subcutaneous, intrauterine, or intramuscular agents). 
 
Participants should be informed that taking the study medication may involve unknown risks to the foetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study they must 
adhere to the contraception requirement (described above) for the duration of the study and during the safety 
follow-up period.  If there is any question that a participant will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study. 
 
6.6.3. Use in Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the participant will 
immediately be removed from the study.  The site will contact the participant at least monthly and document 
the participant’s status until the pregnancy has been completed or terminated.  If the outcome of the 
pregnancy is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn) this will be reported to RM-CTU without delay and within 
24hours of becoming aware of the event to the Sponsor.  The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the foetus or newborn  
to the RM-CTU.   If a male patient impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to RM-CTU and followed as described above and in  
Section 7. 
 
6.6.4. Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, participants who are 
breast-feeding are not eligible for enrolment. 
 

 
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6.7. 
Treatment of Overdose of IMP 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by over 20%. Please see section 7.7 for definitions and reporting procedures. 
6.8. 
Safety Follow-Up Visit 
The mandatory safety follow-up visit should be conducted 30 days after the last dose of trial treatment or 
before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that occur prior to the 
safety follow-up visit should be recorded.  Participants with an AE of Grade > 1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs 
first.  SAEs that occur within 30 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
 
6.9. 
Survival Follow-up 
Once a participant experiences confirmed disease progression or starts a new anti-cancer therapy, the 
participant moves into the survival follow-up phase. Participants will not be expected to attend clinic visits 
during the survival follow-up but information on the participant’s status will be gathered by the research team  
from the participant’s medical notes, the participant’s GP and telephoning the patients directly is applicable. 
The survival period will continue every 12 weeks for 3 years until death, lost to follow up, withdrawal of 
consent or the end of the study. 
 
6.10. 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study 
6.10.1. Permanent Discontinuation of Trial Medication 
A patient may be permanently discontinued from the trial medication for any of the following reasons: 
 The subject withdraws consent. 
 Confirmed radiographic disease progression 
 
 
Note: For unconfirmed radiographic disease progression, please see Section 5.3.8 
 
 
Note: A patient may be granted an exception to continue on treatment with confirmed  
 
 
radiographic progression if clinically stable or clinically improved. 
 Unacceptable adverse experiences as described in Section 6.2 
 Intercurrent illness that prevents further administration of treatment 
 The patient has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 Administrative reasons 

 
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Trial patients will not be replaced or enrolled more than once. The primary reason for discontinuation should 
be recorded on the eCRF. Once the trial medication has been discontinued the patient should complete the 
end of treatment (if applicable) and safety follow-up visit procedures as listed in the schedule of study 
assessments (Table 2). After the end of treatment, patients will continue to be assessed for AE and SAE 
monitoring until completion of the safety follow up visit. 
 
6.11. 
Withdrawal from the Study  
Withdrawal from the study refers to discontinuation of both trial medication and future study visits / 
assessments; this can occur at any time according to the following reasons: 
 Patient decision 
 Lost to follow-up 
 Death 
 PI decision 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of the 
investigator should any untoward effect occur.  In addition, a patient may be withdrawn by the investigator if  
enrolment into the trial is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons. When a patient discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation.  Any adverse events which are present  
at that time should be followed in accordance with the safety requirements outlined in Section 7.  Patients who 
a) attain a CR or b) complete 24 months of treatment with pembrolizumab may discontinue treatment with the 
option of restarting treatment dependant on the investigators clinical judgement.  After discontinuing 
treatment following assessment of CR, these patients should return to the site for a safety follow-up visit and 
then proceed to the survival follow-up period of the study as described in the schedule of study assessments 
(Table 2). 
 
 
7.0. PHARMACOVIGILANCE  
7.1. 
Definition of an Adverse Event (AE) 
An AE is defined as any untoward medical occurrence (including deterioration of a pre-existing medical 
condition) in a patient or clinical trial patient administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom (e.g. nausea, chest pain), signs (e.g. 
tachycardia, enlarged liver) or disease temporally associated with the use of a medicinal product or protocol-

 
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specified procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure.   
 
Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing 
condition that is temporally associated with the use of the pembrolizumab and/or radiotherapy, is also an 
adverse event.  Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of this may 
include, but are not limited to, onset of menses or menopause occurring at a physiologically appropriate time.  
Adverse events 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. 
 
7.1.1. Disease Progression 
Disease progression of the cancer under study is not considered an adverse event unless it results in 
hospitalisation or death. 
 
7.1.2. New Cancers 
The development of a new cancer should be regarded as an SAE and reported accordingly.  
 
7.1.3. Abnormal Laboratory Test Results 
All clinically important abnormal laboratory test results occurring during the study will be recorded as AEs. The 
clinically important abnormal laboratory tests will be repeated at appropriate intervals until they return either 
to baseline or to a level deemed acceptable by the investigator, or until a diagnosis that explains them is made.   
7.1.4. Pregnancy and Lactation 
Pregnancy and lactation are not considered adverse events, however these events should be reported to the 
RM-CTU following guidance in section 7.2.2. 
7.2. 
Assessing and Recording Adverse Events 
All adverse events will be recorded from randomisation until completion of the safety follow-up in the eCRF. 
AEs will be followed up until resolution, stability or it is clinically feasible to do so. The final outcome must not 
only be documented in the eCRF but also recorded in the participants medical records. Serious Adverse Events 

 
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(SAEs) will also be recorded throughout the study until the safety follow-up visit. The reporting timeframe for 
adverse events meeting any serious criteria is described in section 7.5 
 
Any unresolved AEs at the patient’s last visit should be followed up for as long as medically indicated, but 
without further recording in the eCRF.   If an Investigator learns of any SAEs, including death, at any time after a 
patient has completed the study and he/she considers there is a reasonable possibility that the event is related 
to pembrolizumab, the Investigator should notify the RM-CTU. 
The following details will be collected in the eCRF for each AE: 
 AE description / diagnosis 
 Date of onset and date of resolution 
 NCI-CTCAE grade maximum intensity 
 Seriousness 
 Investigator causality rating against the study medication (yes or no) 
 Action taken with regard to study medication 
 Outcome 
In addition, any adverse events occurring during the screening period that are a result of a protocol-specified 
intervention should also be recorded according to guidelines for standard AE reporting. 
 
7.2.1. Evaluating Adverse Events 
AEs will be evaluated by an investigator who is a qualified physician. 
7.2.1.1. Determining AE Severity and Grade 
AE severity and grade will be evaluated according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 4.0 and LENT SOMA radiation toxicity grading system. Any adverse event which changes CTCAE grade 
over the course of a given episode should be closed at the date the severity changed and a new AE recorded on 
the AE e-case report forms from that date at the new severity. 
 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation or 
hospitalisation indicated; disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Table 11: AE severity 
 

 
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7.2.1.2. Determining AE Causality 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE (i.e. IMP, 
other illness, progressive malignancy etc.) and must provide his/her opinion of the causal relationship between 
each AE and IMP.  This may require instituting supplementary investigations of significant AEs based on their  
clinical judgement of the likely causative factors and/or include seeking a further opinion from a specialist in 
the field of the AE. 
 
Causality is the relationship of an AE to the IMP and will be determined as follows; 
Definite: 
There is clear evidence to suggest a causal relationship. 
Starts within a time related to the IMP administration and 
No obvious alternative medical explanation. 
Probable:  
There is evidence to suggest a causal relationship  
Starts within a time related to the IMP administration and 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible:  
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Starts within a time related to the IMP administration  
However, the influence of other factors may have contributed to the event (e.g. the patient’s 
clinical condition, other concomitant treatments). 
Unlikely:  
There is little evidence to suggest there is a causal relationship.  
There is another reasonable explanation for the event (e.g. the patient’s clinical condition, other 
concomitant treatment). 
The time association is such that the trial drug is not likely to have had an association with the 
observed effect. 
Not related:  The AE is definitely not associated with the IMP administered. 
Table 12: Determining causality relationship of AE to an IMP 
   
7.2.2. Reporting of Pregnancy and Lactation  
It is the responsibility of investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them), including the pregnancy of a male patient's female partner that occurs 
during the trial or within 120 days of completing the trial, or 30 days following cessation of treatment if the 
patient initiates new anticancer therapy, whichever is earlier.  All patients and female partners of male patients 
who become pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, foetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.  Such events must be 
reported within 24hours of becoming aware of the event to the Sponsor by Fax 0208 915 6762 who will also 
inform MSD. 
 

 
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7.3. 
Definitions of Serious Adverse Events (SAE) 
An SAE is an AE occurring during any part of the study that meets one or more of the following criteria: 
 
Results in death; 
 
Is life threatening; or places the patient, in the view of the investigator, at immediate risk of death from 
the event as it occurred1 
 
Results in persistent or significant disability/incapacity; 
 
Results in or prolongs an existing inpatient hospitalisation2;  
 
Is a congenital anomaly/birth defect(in offspring of patient taking the product regardless of time to 
diagnosis);  
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with 
an overdose is considered a serious adverse event.  
 
Is an important medical event that may not result in death, not be life threatening, or not require 
hospitalisation but may be considered a serious adverse event when, based upon appropriate medical 
judgment, the event may jeopardise the patient and require medical or surgical intervention to prevent 
such an outcome. 
1 This does not include an AE which hypothetically might have caused death if had it occurred in a more severe form. 
2 Hospitalisation is defined as an unexpected inpatient admission, regardless of length of stay, even if the hospitalisation is a 
precautionary measure for continued observation. It does not usually apply to scheduled admissions that were planned before study 
inclusion or visits to casualty (without admission). 
 
 
7.4. 
Definitions of Evidence of Clinical Interest (ECI) 
Selected non-serious and serious adverse events can also be classified as Events of Clinical Interest (ECI) and 
must be reported as described in section 7.6. 
The following ECIs for this study must be reported to the Sponsor within 24hrs of learning of the event: 
1. An overdose of pembrolizumab, as defined in Section 7.7 that is not associated with clinical symptoms or 
abnormal laboratory results.  
2. A Drug induced liver injury (DILI) defined as elevated AST or ALT lab value that is greater than or equal to 
3X the upper limit of normal  
AND / OR    
An elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal AND / 
OR 
An alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.  
NOTE:  These events will also be reported to MSD by the sponsor. 

 
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3. Any AEs identified in the below table can be classified as immune-related events of clinical interest. A 
detailed narrative of the event should be recorded as an ECI as described in section 7.6: 
 
Pneumonitis  - (deemed as an ECI if ≥ Grade 2 to be reported through the AE reporting pathway ) 
Acute interstitial Pneumonitis 
Interstitial Lung Disease  
Pneumonitis 
Colitis  - (deemed as an ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE to be reported through 
the AE reporting pathway) 
Intestinal Obstruction 
Colitis  
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine  - (deemed as an ECI if ≥ Grade 3 or  ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat the AE and will be 
reported through the AE reporting pathway) 
Adrenal Insufficiency  
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (deemed as an ECI and will be reported through the AE reporting pathway) 
Type 1 diabetes mellitus (if new onset) 
Hematologic - (deemed as an ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the AE and will be 
reported through the AE reporting pathway) 
Autoimmune haemolytic anaemia 
Aplastic anaemia 
Thrombotic thrombocytopenic purpura 
Idiopathic thrombocytopenia purpura 
Disseminated intravascular coagulation 
Haemolytic uraemic syndrome 
Any grade 4 anaemia regardless of underlying mechanism 
Hepatic  - (deemed as an ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE and will be reported 
through the AE reporting pathway) 
Hepatitis 
Autoimmune hepatitis  
Transaminase elevations (ALTand/or AST) 
Infusion reactions - (deemed as an ECI for any grade to will be reported through the AE reporting pathway) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome  
Serum sickness 
Infusion reactions  
Infusion-like reactions  
Neurologic - (deemed as an ECI for any grade and will be reported through the AE reporting pathway) 
Autoimmune neuropathy  
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndromw 
 
 
Ocular  - (deemed as an ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE and will be reported 
through the AE reporting pathway) 
Uveitis 
Iritis 
 
Renal - (reported as ECI for ≥ Grade 2 and will be reported through the AE reporting pathway) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations - (report as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Skin - (deemed as an ECI for any grade and will be reported through the AE reporting pathway) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (deemed as an ECI for ≥ Grade 3 and will be reported through the AE reporting pathway) 
Pruritus 
Rash 
Rash generalised  
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other  - (deemed as an ECI for any grade and will be reported through the AE reporting pathway) 
Myocarditis 
Pancreatitis 
Percarditis 
Any other grade 3 event which is considered immune-related by the physician. 
Table 9: Immune related AEs considered ECIs. 
Patients should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and patients 
should be asked for signs and symptoms suggestive of an immune-related event.  Patients who develop an ECI 
thought to be immune-related should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out 
other etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  

 
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7.5. 
Reporting of SAEs  
Any SAE whether or not related to pembrolizumab, occurring from randomisation until 30 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier, must be reported on 
an SAE report form within 24hours to the Sponsor of the PI or designee becoming aware of the event to the  
via Fax 0208 915 6762 or email to perm.trial@rmh.nhs.uk.  It will be the responsibility of the Sponsor to also 
inform MSD at the same time.   All SAEs regardless of causality, pregnancy (as per section 7.2.2) or overdose (as 
per section 7.7) should be documented and each episode of an SAE must be recorded on a separate SAE report 
form.  The NCI CTCAE Version 4 must be used to grade each SAE, and the worst grade recorded.   
 
If new or amended information on a previously reported SAE becomes available, the Investigator should report 
this to the Sponsor using a new SAE report form. If the SAE has not been reported within the specified 
timeframes, a reason for lateness must be included when sending the SAE report form. Please refer to the SAE 
completion guidelines for further information. 
 
Additionally, any SAE, considered by an investigator (who is a qualified physician) to be related to 
pembrolizumab that is brought to the attention of the investigator at any time outside of the time period 
specified in the previous paragraph also must be reported immediately to the Sponsor who will also inform 
MSD. 
 
7.5.1. Events exempt from being reported as SAEs 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is prolonged 
for any reason and then an SAE form must be completed.  The events must still be recorded in the appropriate 
section of the electronic case report form (eCRF). 
1. Elective admissions to hospital for procedures which were planned and documented in the medical 
records at the time of consent are not SAEs, and do not require SAE reporting.   
2. Hospitalisation for administration of the IMP, or to facilitate study procedures according to the trial 
protocol, is also exempt from being reported as an SAE. 
 
7.5.2. 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 current version of the Investigator Brochure section on Reference Safety Information.  If 
updated versions of the Investigator Brochure are released during the course of the trial then assessment of 
expectedness will be made against the current regulatory approved version. 

 
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7.6. 
Reporting of ECIs 
An ECI, irrespective of etiology or whether or not related to the Pembrolizumab, occurring from the first dose 
until 30 days following the last treatment dose, or the initiation of a new anticancer therapy, whichever is 
earlier; must be recorded on the AE eCRF.   ECIs as described in Section 7.4  should be reported within 24 hours 
of the PI/designee becoming aware of the event to the sponsor.  Please refer to the current Investigator 
Brochure for further information in the Reference Safety Information section.  All other ECIs described in Table 
10 will be reported as per adverse event reporting pathways. 
 
7.7. 
Definition of an Overdose for This Protocol and Reporting of Overdose 
At present no specific information is available on the treatment of overdose of pembrolizumab. For purposes 
of this trial, an overdose will be defined as any dose exceeding the prescribed dose for pembrolizumab by 20% 
over the prescribed dose. In the event of overdose the patient should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the adverse event(s) 
should be recorded on the AE eCRF and documented in the patients’ medical records. The AE should also be 
reported as a serious adverse event, even if no other seriousness criteria are met.   If an overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is again recorded as an 
AE on the eCRF and reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.” 
 
All reports of overdose either SAE or ECI must be reported within 24 hours of the PI or designee becoming 
aware of the event to the Sponsor via Fax 0208 915 6762 who will also inform MSD. 
 
7.8. 
Definition of a Serious Adverse Reaction (SAR) 
A SAR is defined as a SAE that is judged to be related to any dose of study drug administered to the patient. 
7.9. 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) 
A SUSAR is any SAR that is NOT consistent with the applicable product information as set out in the current 
Summary of Product Characteristics (SPC).  
7.10. 
Reporting of SUSARs 

 
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The Investigator and local study team will rapidly report all SUSARs to the Sponsor within 24 hours of becoming 
aware of the event.  The Sponsor will ensure that SUSARs are notified to the appropriate Regulatory Authority, 
the relevant Research Ethics Committee (REC)/Regulatory Authority (RA), MSD, the Sponsor and the 
participating Principal Investigators as appropriate in accordance with regulatory requirements and within the 
required timelines.  Follow up of patients who have experienced a SUSAR should continue until recovery is 
complete or the condition has stabilised. 
7.11. 
Annual Reporting of Serious Adverse Events 
Annual reports will be submitted to the RA and REC by the Sponsor in accordance with all applicable global 
laws and regulations. Copies will be forwarded to the Sponsor and Investigators. 
 
7.12. 
Urgent Safety Measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect the 
patient of a clinical trial against any immediate hazard to their health or safety.  This includes procedures taken 
to protect patients from pandemics or infections that pose serious risk to human health. USMs may be taken 
without prior authorisation from the competent authority. The Medicines and Healthcare products Regulatory 
Agency (MHRA) and the Research Ethics Committee (REC) must be notified within three days of such measures 
being taken.  Should the site initiate a USM, the Investigator must inform RM-CTU either by: 
 
Email:  
Perm.trial@rmh.nhs.uk  
 
Telephone: 
0208 915 6666 
 
Fax: 
 
0208 915 6762 
The notification must include:  
• the date of the USM  
• who took the decision; and  
• why action was taken 
RM-CTU will then inform the Sponsor who will notify the MHRA and the REC immediately and in writing within 
three days of USM initiation.  RM-CTU will distribute the response and any subsequent amendments to the trial 
sites. 
 
CI Contact Details: 
Name:  
Dr James Larkin 
Address: 
Renal and Melanoma Unit 
 
 
The Royal Marsden NHS Foundation Trust 
 
 
203 Fulham Road 

 
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London SW3 6JJ 
Tel: 
 
0208 915 6666   
Fax: 
0208 915 6762 
Email:  
perm.trial@rmh.nhs.uk  
 
 
8.0. STATISTICAL ANALYSIS  
8.1. 
Statistical Analysis Plan Summary 
This is a multicentre, open label, randomised phase II study to assess the efficacy of pembrolizumab alone and 
in combination with high dose radiotherapy. Patients will be randomised into either arm of the study in a 1:1 
ratio and stratified to take account of their baseline LDH and previous anti-CTLA4 treatment. 
 
8.2. 
Sample Size and Power Considerations 
The sample size of this study was calculated using a 2-sided α of 5%; power of 80%; RECIST response rate in the 
pembrolizumab arm is 30%; RECIST response rate in the pembrolizumab and radiotherapy arm is 50%.  The 
study will randomise 234 patients in total (210 minimally required for statistical power calculation purposes, 
105 patients in each arm; 20 additional patients to account for potential drop outs – an expected drop out rate 
of 10%) over 18 months i.e. 11-12 patients per month in approximately 15 to 24 UK centres. In the event that 
enrolment is slower than expected the Trial Steering Committee will consider adding additional UK sites. 
Patients enrolled in the trial are expected to be recruited from the routine clinics of the participating centres. 
 
8.3. 
Randomisation 
Patients will be randomised in a 1:1 ratio to receive pembrolizumab alone or pembrolizumab in combination 
with radiotherapy using random permuted blocks within strata to take account of their LDH level at baseline 
and previous anti-CTLA4 treatment.  
Randomisation of enrolled patients will be stratified based on the following parameters; 
1. LDH (below or within normal range / above upper limit of the normal range) and  
2. Previous anti-CTLA4 treatment (yes/no)  
The randomisation number is a unique number.   Patients will be identified using the number generated by the 
database which will become their unique identifier throughout the study and in all future correspondence..  
 
8.4. 
Data Analysis  
The clinical data will be entered and stored in the PERM electronic database. Statistical analysis will be 
conducted using STATA software version 13.  

 
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8.4.1. Analysis populations 
The efficacy results of the trial will be analysed on an intention to treat (ITT) basis. The ITT population is defined 
as all patients randomised in the study and are analysed as randomised for response rate, PFS and OS. 
The safety data will be analysed by treatment received, irrespective of randomisation, in patients who received 
at least one treatment dose. Patients withdrawn prior to the first treatment dose will be excluded. 
 
In addition, after 50% of the patients have been randomised and are evaluable for the primary endpoint an 
interim analysis will be carried out to assess the difference between the two trial arms.  In the event that both 
arms showed a RECIST response rate of 30% when approximately 120 patients are evaluable then it will be 
judged unlikely that the pembrolizumab and radiotherapy arm will show a RECIST response rate of 50% relative 
to the 30% RECIST response rate in the pembrolizumab only arm at the end of the trial and the trial will be 
stopped. 
 
Furthermore when 50% of the patients have been recruited this will be reviewed by the independent members 
of the TSC only, within a closed session.  They will also decide if the results of the analysis needs to be released 
to the TMG, and whether any changes to the study should be implemented in terms of its continuance 
 
8.4.2. Study Endpoints 
Primary Endpoint: 
 
The difference in RR between the treatment arms will be calculated at 12 weeks post treatment start in 
the ITT population. This will be presented using the percentage of patients, including 95% confidence intervals,  
who achieve CR or PR according to the RECIST v1.1 criteria in each treatment group. Analysis of the primary 
endpoint will be carried out when all patients have completed treatment and 12 week follow-up assessments. 
 
Secondary Endpoints: 
 
To determine RR at 6 months post treatment start. This is defined as the percentage of patients  
 
achieving confirmed PR or CR as per RECIST v1.1 in the ITT population. 
 
To measure individual lesion response assessment every 12 weeks taking account of within patient  
 
data. Individual lesion response for each patient will be measured over time by assessing PR, CR or SD  
 
as per RECIST v1.1 at each time point. 
 
Toxicity will be graded according to CTCAE version 4.0 and LENT SOMA radiation toxicity grading  
 
system after 12 weeks of treatment. 
 
PFS will be calculated at 1, 2 and 3 years from treatment start until PD or death from any cause.  

 
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Patients  alive and progression free will be censored at 1, 2 and 3 years, and those patients who are lost  
 
to follow-up, withdrawn from follow-up will be censored at the date of last assessment whichever is  
 
sooner, respectively. 
 
OS will be calculated from treatment start until date of death from any cause. Patients, in whom no  
 
death is recorded, will be censored at the date they were last seen alive. 
 
Exploratory Endpoints: 
Peripheral blood analysis 
Peripheral blood collected from patients at baseline, during and follow-up of treatment will be analysed to 
assess immune function in response to pembrolizumab ± radiotherapy.  Assays to examine innate and/or 
adaptive immune functional response may include, for example, immunophenotyping, cytokine/chemokine 
arrays.  For details, refer to the associated Trial Manual. 
 
Tumour Biopsy samples 
Tumour biopsy tissue collected from patients at baseline & during treatment will be examined to assess the 
tumour microenvironment in response to therapy.    Tumour may be used in, for example, multi-colour 
immunohistochemistry and RNA sequence analysis to investigate TIL infiltration & expression of known 
tumour-associated antigens.  For details, refer to the associated Trial Manual. 
 
8.5. 
Planned method of analysis 
Continuous data will be summarised using means, standard deviations, medians, minimum and maximum 
values and where appropriate 95% confidence intervals. Nominal and ordinal categorical data will be 
summarised using the number of observations and percentages.  All significance tests will be two-sided using 
an overall alpha level of 5%. It is anticipated that adjustment will be made for repeated significance testing 
using a Bonferroni correction specifically for all secondary endpoints.  
 
Primary Endpoint:  
 
The RR 12 weeks post treatment will be summarized as the percentage (including 95% confidence 
intervals) of responders and will be compared between treatment arms using the chi-squared test for 
proportions.  
Secondary Endpoints: 
 
The RR at 6 months will be summarized as a percentage (including 95% confidence intervals) of 
responders and will be compared between treatment arms using the chi-squared test for proportions. 

 
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 
To measure individual lesion response assessment every 12 weeks within each patient using 
McNemar’s test of paired proportions between time points. 
 
The proportion of patients experiencing grade 3-5 toxicity will be compared on a regimen basis using 
the chi-squared test. Fishers exact test will be used when expected cell frequencies are <5.  
 
PFS and OS at 1, 2 and 3 years, respectively, will be calculated using Kaplan-Meier methods. Median 
PFS and OS with associated 95% confidence intervals will be presented by treatment and compared 
using the log rank test. Cox Proportional hazards regression model analysis will be used to calculate the 
hazard ratio between treatments along with its 95% confidence intervals and will be adjusted for other 
identified prognostic factors in a multivariate setting. 
 
Exploratory Endpoints: 
 
Continuous exploratory data will be summarised using means, standard deviations, medians, minimum 
and maximum values attaching 95% confidence intervals where appropriate. Categorical data will be 
summarised using frequencies and proportions, attaching confidence intervals where necessary.  
 
8.5.1. Safety Review Meeting 
To ensure the safety of the patients an assessment of toxicity of the first 6 randomised to receive both 
pembrolizumab and radiotherapy will be performed when they have completed 12 weeks of treatment. A 
listing of AEs will be produced for these patients identifying toxicity grades after they have completed 12 weeks 
of treatment. 
8.6. 
Deviations from the Statistical Plan 
Statistical methods to handle deviations from protocol (e.g. changes in final sample size) will be described in 
the analysis plan. The analysis plan of the handling and analysis methods of secondary variables may be  
updated following review of data during the study. The statistical analysis plan will be finalised / approved prior 
to the analysis. Deviations in implementation of the finalised analysis plan will be documented for affected 
results in the clinical study report. 
 
8.7. 
Early Discontinuation of the Study  
An interim analysis will be carried out when approximately 120 patients (50%) are evaluable for the 
primary endpoint, this will allow for the early termination of the trial should there be no difference 
between the two arms, respectively. No formal stopping rules are planned either for efficacy, futility 
or toxicity since this study is similar to routine standard of care with the addition of radiotherapy.  The 

 
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Trial Steering Committee will monitor trial progress including for significant safety / toxicity issues 
should they arise.   
 
9.0. 
REGULATORY, ETHICAL AND LEGAL ISSUES 
9.1. 
Good Clinical Practice 
The study will be conducted in accordance with the conditions and principles of GCP as defined in the clinical 
trials regulations. .  
9.2. 
Research Ethics Committee (REC)/Regulatory Authority (RA) 
9.2.1. Initial Approval 
Before starting the trial, the protocol, patient information sheet, consent form, any other written information 
that will be provided to the patients and any advertisements that will be used and details of any patient 
compensation must be approved by the Royal Marsden/Institute of Cancer Research joint Committee for 
Clinical Research.  Once approved, the study will then be submitted to the relevant Ethics Committee for their 
review and approval.   
 
Prior to the shipment of IMP and the enrolling any patients the Investigator at each site is responsible for any 
site specific assessments and obtaining local R&D approval for the study .  All participating sites will be required 
to sign an agreement with RM-CTU which includes requirement to sign and adhere to the trial protocol. 
 
9.2.2. Approval of Amendments  
Any protocol amendment should be agreed with the trial management group (TMG) and be approved by the 
sponsor prior to submission and review by the relevant Ethics Committee.  Once favourable opinion from IEC 
has been obtained the amendment can be distributed to sites and implemented.  It is the responsibility of the 
Principal Investigator to submit amendment to their R&D department for R&D approval Amendments requiring 
REC approval may be implemented only after a copy of the REC/RA’s approval letter has been obtained. 
Amendments that are intended to eliminate an apparent immediate hazard to patients may be implemented 
prior to receiving Sponsor or REC/RA approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
9.2.3. Annual Safety Reports and End of Trial Notification 
It is the responsibility of the sponsor to submit the Development Safety Update Report annually to the MHRA/ 
REC on the anniversary of the studies MHRA/REC approval. This will facilitate the authorities continuing review 

 
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of the study. These authorities will also be informed of the end of the study by the sponsor within 90 days of 
the trial completion.   Copies of these reports will also be held within the main trial master file. 
9.3. 
Regulatory Authority Approval 
The study will be performed in compliance with UK regulatory requirements. Clinical Trial Authorisation (CTA) 
from the Medicines and Healthcare products Regulatory Authority (MHRA) will be obtained prior to the start of 
the study. In addition, the MHRA must approve amendments (as instructed by the Sponsor), receive SUSAR 
reports and annual safety updates, and be notified of the end of the trial. 
9.4. 
Notifications of Serious Breaches to GCP and / or the Protocol 
The Sponsor will notify the MHRA and REC in writing of any serious breaches of: 
a. The condition and principles of GCP in connection with the trial 
b. The protocol 
This will be done within 7 days if becoming aware of that breach, in accordance with the applicable UK 
regulations as amended from time to time. 
For the Purpose of the regulations a “serious breach” is a breach which is likely to effect to a significant degree 
a. The safety or physical integrity of the subjects of the trial; or 
b. The scientific integrity of the trial. 
Systematic or persistent non-compliance by the site with GCP and/or the study protocol, including failure to 
report SAEs occurring on trial within the specified timeframes, may be deemed a serious breach. 
 
9.5. 
Insurance and Liability 
The Sponsors have secured indemnity from the manufacturer of pembrolizumab for patients in relation to 
adverse side effects for medicine-induced injury. Indemnity for participating hospitals is provided by the usual 
NHS indemnity arrangements for clinical negligence.  A copy of the relevant insurance policy/indemnity scheme 
or summary shall be provided on request. 
9.6. 
Contact with General Practitioner (GP) 
It is the Investigator’s responsibility to inform the patient’s GP by letter that the patient is taking part in the 
study provided the patient agrees to this, and information to this effect is included in the PIS and ICF. A copy of 
the letter should be filed in the Site File. A template letter approved by the REC/RA will be provided by the 
Sponsor to all participating sites. 

 
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9.7. 
Patient Confidentiality 
9.7.1. Patient Confidentiality and Data Sharing  
The Principal investigator must ensure that the patient’s confidentiality is maintained in compliance with the 
UK Data Protection Act 1998.   In all study correspondence submitted to the RM-CTU (apart from signed 
consent forms) all participants will be identified by their initials and unique Trial Reference study number only 
which will be used in all e-CRFs or other documents submitted to the RM-CTU.  
 
In compliance with GCP guidelines, it is required that the investigator and institution permit authorised 
representatives of the sponsor and of the regulatory agency(s) direct access to review the patient’s original 
medical records for verification of study-related procedures and data. Direct access includes examining, 
analysing, verifying, and reproducing any records and reports that are important to the evaluation of the study. 
The investigator is obligated to inform and obtain the consent of the patient to permit named representatives 
to have access to his/her study-related records without violating the confidentiality of the patient.  In addition 
to this, anonymised images will be sent via a secure network to the approved Radiotherapy Quality Assurance 
team. 
 
9.7.2. Pharmacogenetics Confidentiality  
All pharmacogenetic samples and the information associated with the samples will be coded and stored 
appropriately to ensure confidentiality of the patient’s information and to enable destruction of the samples if 
requested.   Since the evaluations are not expected to benefit the patient directly or to alter the treatment 
course, the results will not be placed in the patient’s medical record and will not be made available to members 
of the family, the personal physician, or other third parties, except as specified in the informed consent.  
 
9.8. 
Data collection and documentation 
It is the Investigator’s responsibility to ensure that all relevant data is clearly recorded in the medical records.  
The Investigator must allow the RM-CTU direct access to relevant source documentation for verification of data 
entered into the e-CRF, taking into account data protection regulations. The clinical data should be recorded in 
the e-CRF and the must be verifiable by the source data. 
 
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the sponsor appointed to audit the trial, or by REC.  Details will remain 
confidential and patients’ names will not be recorded outside the hospital. 
 
The Principal Investigators at each centre are confirming agreement with his/her local NHS Trust to ensure that  

 
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 sufficient data is recorded for all participating patients to enable accurate linkage between hospital 
records and e-CRFs  
 source data and all trial related documentation are accurate, complete, maintained and accessible for 
monitoring and audit visits  
 original consent forms are dated and signed by both patient and investigator and are kept together in a 
central log together with a copy of the specific patient information sheet(s) given at the time of consent  
 all essential documents must be retained after the trial ends to comply with current legislation  
No study document will be destroyed without prior written agreement between the Sponsor and the PI. Should 
the PI wish to assign the study records to another party or move them to another location, written agreement 
must be obtained from the Sponsor. 
9.9. 
End of Trial 
The end of the trial is defined as the last patient’s last visit. 
 
 
10.0. DATA AND STUDY MANAGEMENT  
10.1. 
Source Data 
All information in original records and certified copies of original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial are classified as 
source data. Source data are contained in source documents; these are defined as original documents, data, 
and records e.g., hospital records, clinical and office charts, laboratory notes, memoranda, patients' diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial.  
10.2. 
Language 
All e-CRFs will be in English. Generic names for concomitant medications should be recorded in the CRF 
wherever possible. All written material to be used by patients must use vocabulary that is clearly understood, 
and be in the language appropriate for the study site. 
10.3. 
Data Collection 
The medical records/medical notes should be clearly marked and to allow for easy identification of a patient’s 
participation in the clinical trial. The Investigator (or delegated member of the site study team) must record all 

 
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data relating to protocol procedures, IMP administration, laboratory data, safety data and efficacy data into 
the e-CRF.  
 
10.4. 
Electronic Recording of Data 
Patients’ data will be documented on a trial specific e-CRF designed by RM-CTU. Should the eCRF not be 
available before the study is ready to begin paper CRFs will be used until the switch can be made.  Upon signing 
the informed consent form, the patient is assigned to the next sequential Patient screening number available. 
Following confirmation of eligibility patient will be randomized and assigned a randomization number. 
 
The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the data 
reported in the e-CRFs.  Only the Investigator, and those personnel who have completed the Study Team 
Responsibilities Signature Log/Delegation Log as authorised by the PI, should enter or change data in the e-
CRFs.  All protocol required investigations must be reported in the e-CRF.  The Investigators must retain all 
original reports, traces and images from these investigations for future reference.  The data will be entered in a 
clinical trials database (Macro V4).  If a patient withdraws from the study, the reason must be noted on the e-
CRF.  
 
Authorised site personnel must not enter study-specific data directly into e-CRFs and ensure all results are 
appropriately documented in the patients’ medical records. The e-CRF will be signed electronically by the 
Investigator or by an authorised staff member. Study specific information will be entered into an e-CRF visit by 
visit. Data that are derived should be consistent with the source documents or the discrepancies should be 
explained.   All e-CRF data should be anonymous, i.e. identified by study patient number only. 
 
10.5. 
Data Management 
Data management will be carried out by RM-CTU using an electronic database and in accordance with the data 
management plan agreed by the RM-CTU and RDSU. Data entry will be carried out by appropriately trained 
personnel at participating centres. Queries will be raised centrally by the trial manager / trial monitor and sent 
to the participating centre for resolution.  
 
10.6. 
Study Management Structure 

 
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10.6.1. Delegations of Responsibilities  
This trial is sponsored by the Royal Marsden.  This trial will be conducted in accordance with the professional 
regulatory standards required for non-commercial research in the NHS under the research governance 
framework for health and social care and good clinical practice.  The following responsibilities have been 
delegated to: 
 
10.6.1.1. 
RM-CTU 
RM-CTU has overall responsibility for facilitating and coordinating the conduct of the trial and is also 
responsible for collating data obtained, and undertaking and reporting all analyses.  
The responsibilities of RM-CTU for the day-to-day management of the trial will include the following;  
 ensuring an appropriate ethics opinion has been sought, and any amendments have been approved  
 giving notice of amendments to protocol, make representations about amendments to the Main REC  
 
and MHRA as applicable 
 notifying sites and Sponsor that the trial has ended  
 randomising patients  
 raising and resolving queries with local investigators  
 keeping records of all serious adverse events (SAEs), overdose incidents, pregnancies and ECI’s  
 
reported by investigators (as outlined in section 7.4 above) 
 notifying the Main REC, MHRA and Investigators of related Serious Adverse Events  
 
10.6.1.2. 
Merck, Sharp & Dohme Corp. 
Provision of pembrolizumab. 
 
10.6.1.3. 
Participating Sites  
Responsibilities are defined in an agreement between an individual participating sites and the sponsor, which 
must be signed and in place prior to recruitment commencement.  Also (but not limited to);  
 putting and keeping in place arrangements to adhere to the principles of GCP keeping a copy of all  
 ‘essential documents’ (as defined under the principles of GCP) in an Investigator  Site and Pharmacy 
File and ensuring appropriate archiving of all essential documentation once the trial has ended  
 taking appropriate urgent safety measures 
 Sites wishing to participate in this study will be required to provide evidence that they can are  
 
equipped to deliver the protocol treatment for the duration of the study. 
 

 
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10.7. 
Protocol compliance and amendments 
All participating sites will be required to sign an agreement with RM-CTU which includes requirement to sign 
and adhere to the trial protocol. 
 
Any protocol amendment should be agreed with the trial management group (TMG) and be approved by the 
sponsor prior to submission and review by the relevant Ethics Committee and the MHRA where required.  Once 
Favourable Opinion from REC and if applicable the MHRA has been obtained the amendment may be 
disseminated to sites and implemented.  It is the responsibility of the Principal Investigator to submit 
amendment to their R&D department for R&D approval. 
 
10.8. 
Trial Management  
The RM-CTU will be responsible for the day-to-day coordination and management of the trial. This includes all 
duties relating to safety reporting.  A trial agreement will be signed between the site and RM-CTU. Once all 
relevant trial approvals are in place an initiation (visit or teleconference) will be conducted.  In addition, 
training and ongoing advice will be provided by trial training workshop(s), site initiation and ongoing site 
support to each participating site by Trial Management Group (TMG).   
 
10.8.1. Trial Management Group 
A Trial Management Group (TMG) will be set up and membership will include Chief Investigator, Chief Co 
Investigator, Trial Statistician and Trial Manager. Principal Investigators and other key study personnel will be 
invited to join the TMG as appropriate. The TMG have operational responsibility for the conduct of the trial.  
 
10.8.1.1. 
Safety Review Meetings 
At the beginning of the study the TMG will meet every 2 weeks until the first 6 patients randomised to receive 
both pembrolizumab and radiotherapy have completed 12 weeks of treatment to review any safety aspects 
relating to the trial. 
Once all 6 patients have completed 12 weeks of treatment a safety assessment will be conducted reviewing all 
AE’s, SAE’s and radiation toxicities occurring in this population. 
10.8.2. Trial Steering Committee (TSC) 
A trial steering committee (TSC) will be established at the start of the trial.  The TSC will be chaired by an 
independent chair and include the Co-chief investigators (Dr Larkin and Dr Nathan).  Other independent 

 
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members (1-2 including a melanoma expert and statistician) will be appointed prior to the start of the study.  
The TSC will also take on the role of IDMC as part of a closed session without Drs Larkin and Nathan.  
 
The role of the TSC is to monitor trial progress and to ensure the protocol and GCP principles are adhered to. 
The TSC’s terms of reference, roles and responsibilities will be defined in a charter.  Further internal or external 
experts may be consulted by the TSC as necessary. 
 
10.9. 
Monitoring 
During the trial RM-CTU is responsible for monitoring data quality in accordance with relevant standard 
operating procedures (SOPs).  Incoming data will be monitored for protocol compliance and if any inconsistent 
or missing data is identified queries will be sent to the site for resolution.  Any systematic inconsistencies may 
trigger an onsite monitoring visit. 
 
The trial statistician will periodically examine the data for anomalies and outliers, such as too few or too many 
events. Queries will be raised by the trial coordinators in such situations and communication with the clinical  
teams will take place. In addition statistical monitoring of unusual dates and inconsistent data will take place. 
Again these will raise queries via the trial coordinators. 
 
If an on-site monitoring visit is required, RM-CTU will contact the site to agree convenient date.  The site must 
ensure that relevant site file and patient notes are available for review.  RM-CTU staff conducting onsite 
monitoring will review the investigator site file and carry out source data verification to confirm compliance 
with the protocol, trial agreement. 
 
10.10. Quality Control and Quality Assurance 
Quality Control (QC) will be performed according to RM-CTU internal procedures. The study may be audited by 
a Quality Assurance (QA) representative of the Sponsor. All necessary data and documents will be made 
available for inspection. 
 
10.11. Clinical study report 
Clinical data will be presented at the end of the trial based on final data listings.  The CI/designee together with 
the trial statistician will prepare a brief clinical study report / publication based on the final data listings.  A 
summary of the report must be provided to the Research Ethics Committee and the MHRA within 1 year from 
the submission of the end of trial notification. 
 

 
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10.12. Record retention 
Essential documents are documents that individually and collectively permit evaluation of the conduct of the 
trial and substantiate the quality of the data collected. During the clinical trial and after trial closure the 
Investigator must maintain adequate and accurate records to enable both the conduct of a clinical trial and the 
quality of the data produced to be evaluated and verified in accordance with current legislation.   
 
RM-CTU will maintain essential documents to facilitate the management of the trial, audit and inspection in 
accordance with RM G-SOPs and in compliance with the clinical trial regulatory requirements.   The medical 
files of trial subjects shall be retained in accordance with national legislation and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. All medical records and TMF 
documentation will be retained for a minimum of 5 years after the study has concluded. 
 
10.13. Reporting and publication 
The trial results will be submitted for publication in a relevant medical journal with authorship according to the 
criteria defined by the ICMJE (http://www.icmje.org). These state that: Authorship credit should be based 1) 
substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; 
2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the 
version to be published. Authors should meet conditions 1, 2, and 3.  
 
Draft publications (manuscripts, abstracts, slides and posters) should be submitted to the RM-CTU for 
circulation to the relevant parties to allow sufficient time for review prior to submission. There will be a fifteen 
(15) day period to review abstracts or posters and a thirty (30) day period to review slides and manuscripts and 
respond to the author with any revisions. 
 
10.14.  Ethical considerations 
Before starting the trial, the protocol, patient information sheet and consent form must be approved by the 
RM/ICR joint Committee for Clinical Research.  Once approved, the study may then be submitted to the 
relevant regulatory authorities. 
 
It is the Chief and Principal Investigator’s responsibility to update patients (or their authorised representatives, 
if applicable) whenever new information (in nature or severity) becomes available that might affect the 
patient’s willingness to continue in the trial.  The Chief and Principal Investigator must ensure this is 
documented in the patient’s medical records and the patient is re-consented, where appropriate. 
 

 
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The Sponsor and Chief and Principal Investigator must ensure that the trial is carried out in accordance with the 
GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 2006/1928 as 
amended) and The Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/). 
 
 
11. REFERENCES 
 
1. 
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
2. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumour-associated B7-H1 promotes T 
cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8(8):793-800.   
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of programmed death-1 
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35. Dovedi SJ, Melis MH, Wilkinson RW, Adlard AL, Stratford IJ, Honeychurch J, Illidge TM. Systemic delivery of 
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42. Stamell E, Wolchock J, Gjatic S et al. The Abscopal Effect Associated with a Systemic Anti-Melanoma 
Immune Response. International Journal of Radiation Oncology,  Biology and Physics 2013; 85(2): 293-295 
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Oncology 2012; 5(6):404-407 
 
 
 
 

 
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APPENDICES 
APPENDIX 1 - Common Terminology Criteria For Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilised for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 2: LENT SOMA Scales for all Anatomical Sites 
 
This study will utilize the LENT SOMA radiation toxicity grading system (Int. J. Radiation Oncology Biol. Phys., 
Vol. 31, No. 5, 1049-1091, 1995).  
All appropriate treatment areas should have access to a copy of the current LENT SOMA scoring system. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 3: Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumours 
 
RECIST version 1.1* will be used in this study for assessment of tumour response. While either CT or MRI may 
be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, 
L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 4: Identification, evaluation and management of ECIs 
ECI 
Grade 
Action to be taken 
Supportive Care 
 
Pneumonitis –  
 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours 
 
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 
 
Report as ECI within 24 hours 
 
Discontinue pembrolizumab 
 
Hospitalize 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 ECI guidance document v5.0. 
 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 as ECI within 24 hours 
 
Withhold pembrolizumab, may restart 
if Grade 1 or resolved within 12 weeks 
 
Symptomatic treatment 
 
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. 
Grade 3 
 Report as ECI within 24 hours 
 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 that 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 ECI 
guidance document v5.0. 
Grade 4 
 Report as ECI within 24 hours 
 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 
 
Report as ECI if appropriate - see ECI v5 
guidance. 
 
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 
 
Report as ECI within 24 hours 
 
Withhold pembrolizumab, may restart 
if Grade 1 or resolved within 12 weeks 
 
IV methylprednisone 1-2mg/kg followed by 
prednisone 1-2mg/kg per day.  
 
Symptoms grade 1 or less initiate steroid taper for no 

 
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 
Rule out infection and sepsis. 
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 
 Report as ECI within 24 hours 
 Discontinue pembrolizumab 
 Manage as per grade 3 
Endocrine – 
Hypophysitis or 
other symptomatic 
endocrinopathy 
Grade 1 
(Asymptomatic) 
 
No action 
Intervention not indicated 
Grade 2 – 4  
 
Report as ECI if appropriate - see ECI 
v5 guidance. 
 
Withhold pembrolizumab 
 
Rule out infection and sepsis. 
 
Monitor thyroid function until 
returned to baseline. 
 
Consider pituitary gland imaging  
 
Hypophysitis with clinically significant 
adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities 
(such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
 
Consider endocrinologist consult. 
 
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. 
Type 1 Diabetes 
Mellitus and ≥ 
Grade 3 
hyperglycaemia 
Type 1 Diabetes 
Mellitus and ≥ grade 
3 hyperglycaemia 
 
Report as ECI if appropriate see Table 
11 
 
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 3-4 
hyperglycaemia associated with metabolic acidosis or 
ketonuria.  
 
Evaluate patients with serum glucose and a metabolic 
panel, urine ketones, glycosylated haemoglobin, and C-
peptide. 
Hematologic 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours 
 
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 
 
Report as ECI within 24 hours 
 
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 
 
Report as ECI within 24 hours 
 
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 ECI 
guidance for 
definitions of (DILI) 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours 
 
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. 
 
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 as ECI within 24 hours 
 
Discontinue pembrolizumabif AST or 
ALT > 5.0 X ULN and/or total bilirubin is 
>3.0 X ULN 
 
Consider consultation and biopsy to 
establish etiology  
 
High dose IV glucocorticosteroids for 24-48hours.  
 
Symptoms grade 1 or less initiate steroid taper for no 
less than 4 weeks 
 
 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 additional guidance 
in the ECI guidance document. 

 
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 
Permanently discontinue pembrolizumab is if dose 
cannot be reduced to prednisone 10mg or less or 
equivalent per day within 12 weeks. 
Grade 4 
 
Report as ECI within 24 hours 
 
Discontinue pembrolizumab 
 
Manage as per grade 3 
Neurologic 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours  
 
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 
 
Report as ECI within 24 hours  
 
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 
 
Report as ECI within 24 hours  
 
Evaluation by ophthalmologist 
recommended  
 
Topical steroids – 1%prednisolone acetate 
suspension and iridocyclitics 
 
Permanently discontinue IF symptoms persist despite 
treatment. 
Grade 3 
 
Report as ECI within 24 hours  
 
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 
 
Report as ECI within 24hours  
 
Evaluation by ophthalmologist 
recommended 
 
Permanently discontinue 
pembrolizumab  
 
Manage as per grade 3 
Renal 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours  
 
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 
 
Report as ECI within 24 hours  
 
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 glucocoticosteroids or urea 
containing cream in combination with oral anti-pruritics 
 
Treatment with oral steroids at PIs 
discretion 
Grade 3 
 
Report as ECI within 24 hours  
 
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 
 
Report as ECI within 24 hours  
 
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, erytema 
mulitforme, 
Stevens Johnson 
Grade 1 
(Asymptomatic) 
 
No action 
 
Intervention not indicated 
Grade 2 
 
Report as ECI within 24 hours  
 
Symptomatic treatment 
 
Topical glucocoticosteroids or urea-containing cream 
in combination with oral anti-pruritics. Treatment 

 
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syndrome, toxic 
epidermal 
necrolysis 
 
Withhold pembrolizumab 
with oral steroids at PIs discretion 
Grade 3 
 
Report as ECI within 24 hours  
 
Withhold Pembrolizumab 
 
Consider dermatology consultation and 
biopsy for diagnosis. 
 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xday.  
 
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 as ECI within 24 hours  
 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:  
Myocarditis 
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 as ECI 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 
 Report as ECI within 24 hours  
 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 
 Report as ECI within 24 hours  
 Discontinue Pembrolizumab 
 
 Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg prednisone or equivalent once per day. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
PERM Study Protocol | RM-CTU 
V4.0 dated 15Feb2017 
                                  CONFIDENTIAL      
           
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