Phase I Dose Escalation of pAlliative Radiotherapy With Anti-PD1 Antibody Pembrolizumab in Thoracic Tumours
Phase: PHASE1
Conditions: Thoracic Tumours
Sponsor: Royal Marsden NHS Foundation Trust

 
 
 
 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 1 of 100                  
 
 
 
 
 
 
                          
PEAR Clinical Study Protocol 
 
 
 
 
 
 
Study Title: 
PEAR: Phase I dose Escalation of pAlliative Radiotherapy with 
anti-PD1 antibody pembrolizumab in thoracic tumours 
Protocol number: 
CCR 4282 
Sponsor: 
Royal Marsden NHS Foundation Trust 
EudraCT number: 
2014-005673-36 
ClinicalTrials.gov 
Identifier: 
NCT02587455 
Product: 
MK-3475/pembrolizumab (KEYTRUDA®) 
Development phase: 
I 
Protocol                            
Version and Date: 
                                                                                                              
V5.1, 19 June 2020 
 
 
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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1 CONTACT LIST 
Chief Investigator: 
 
Dr Merina Ahmed 
Consultant Clinical Oncologist 
Royal Marsden NHS Foundation Trust 
Downs Rd 
Sutton 
SM2 5PT 
Tel: 020 8661 3374  
Email: merina.ahmed@rmh.nhs.uk 
Sponsor: 
 
Royal Marsden NHS Foundation Trust  
Fulham Rd 
London 
SW3 6JJ 
 
Contact Name: 
Ann Gandolfi 
Email: ann.gandolfi@rmh.nhs.uk 
Funder: 
 
 
NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre (BRC) 
 
Merck Sharp and Dohme (MSD) 
 
Trial Manager: 
 
Royal Marsden Clinical Trials Unit (RM-CTU) 
Royal Marsden NHS Foundation Trust 
Downs Rd 
Sutton 
SM2 5PT 
 
Contact Name: 
Sarah Webb 
Tel: 020 8915 6508 
Email:  sarah.webb2@rmh.nhs.uk 
 
 
 

 
 
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2 
PROTOCOL DEVELOPMENT TEAM 
 
Dr Diana Tait – Co-Investigator 
Consultant Clinical Oncologist 
Royal Marsden NHS Foundation Trust 
Diana.Tait@rmh.nhs.uk 
 
Dr Mary O’Brien – Co-Investigator 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Mary.O’Brien@rmh.nhs.uk 
 
Dr Sanjay Popat – Co-Investigator 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Sanjay.Popat@rmh.nhs.uk 
 
 
Ranga Gunapala – Senior Statistician 
RDSU 
Royal Marsden NHS Foundation Trust 
ranga.gunapala@rmh.nhs.uk 
 
Dr Rajiv Kumar – Co-Investigator 
Clinical Research Fellow 
Royal Marsden NHS Foundation Trust 
Rajiv.Kumar@rmh.nhs.uk 
 
 
Dr Charlotte Milner-Watts – Co-Investigator 
Clinical Research Fellow 
Royal Marsden NHS Foundation Trust 
Charlotte.Milner-Watts@rmh.nhs.uk  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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3 
PROTOCOL SIGNATURES 
Chief / Principal Investigator Signature: 
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 Regulations, the guidelines of Good Clinical Practice (GCP) the Declaration of 
Helsinki, 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 that 
will be involved in the trial, and ensure that all staff members are aware of their clinical trial responsibilities. 
Chief Investigator Name: 
 
Signature: 
 
Date: 
 
 
 
Statistician Signature: 
The signatures below constitute approval of this protocol by the signatory. 
Sponsor Representative Name: 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 TRIAL SUMMARY 
Title 
PEAR: Phase I dose Escalation of pAlliative Radiotherapy with anti-PD1 antibody 
pembrolizumab in thoracic tumours 
Abbreviated Title 
Pembrolizumab and palliative radiotherapy in lung 
Trial Phase 
Phase I 
Clinical Indication 
The treatment of patients with non-small cell carcinoma (NSCLC) of lung requiring 
palliative radiotherapy (RT) to the chest for which no curative therapy exists 
Trial Type 
Interventional 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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Type of control 
No treatment control 
Route of administration 
Intravenous pembrolizumab and external radiotherapy 
Trial Blinding 
Unblinded, open label, dose escalation phase I study, with a subsequent expansion 
phase 
Treatment Groups  
Part A – Dose escalation stage: 
• 
DOSE LEVEL 1: 
o Low Dose RT Arm: 100mg every 2 weeks at Week 0 and Week 2 then 
followed by maintenance dose of 200mg every 3 weeks starting at week 5. 
o High Dose RT Arm: 100mg every 2 weeks at Week 0, Week 2 and Week 4 
then followed by maintenance dose of 200mg every 3 weeks starting at 
week 6. 
• 
DOSE LEVEL 2: 
o Low Dose RT Arm: 200mg every 2 weeks at Week 0 and Week 2 then 
followed by maintenance dose of 200mg every 3 weeks starting at week 5. 
o High Dose RT Arm: 200mg every 2 weeks at Week 0, Week 2 and Week 4 
then followed by maintenance dose of 200mg every 3 weeks starting at 
week 6. 
• 
DOSE LEVEL -1 (If DLTs are seen at dose level 1): 
o Low Dose RT Arm: 50mg every 2 weeks at Week 0 and Week 2 then 
followed by maintenance dose of 200mg every 3 weeks starting at week 5. 
o High Dose RT Arm: 50mg every 2 weeks at Week 0, Week 2 and Week 4 
then followed by maintenance dose of 200mg every 3 weeks starting at 
week 6. 
 
Part B – Expansion cohort:  
An additional 12 patients will be recruited and will receive High Dose RT and the 
recommended dose determined in part A. 
Number of trial patients 
Approximately 36 patients may be recruited depending on the dose levels tolerated – 
up to 24 patients will be recruited to the dose escalation phase in a 3+3 design, and the 
dose expansion phase will recruit up to 12 patients in total. 
Estimated duration of trial 24months.  
Duration of Participation 
Until disease progression, unacceptable toxicity or withdrawal from the trial.  
Study Objectives 
Primary 
• 
To determine the safety and tolerability of pembrolizumab in combination with RT 
to the lung. 
Secondary 
• 
To assess overall progression free survival (PFS) and overall survival (OS). 
• 
To evaluate PFS in a PD-L1 strong population. 
• 
To assess overall responses rates as per RECIST v1.1 and differential responses rates 
in squamous versus non-squamous histological subtypes. 
• 
To assess oesophagitis rates in this population. 
Exploratory 
• 
To assess for evidence of abscopal response. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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• 
Identification of biomarkers that correlate with immunological response to therapy. 
Study Endpoints 
Primary 
• 
To establish the maximum tolerated dose (MTD) that can be safely combined with 
RT in the absence of dose limiting toxicity (DLT). 
• 
To measure the toxicity rate of pneumonitis at grade ≥2 assessed two months after 
the last fraction of RT has been administered. 
Secondary 
• 
To measure the PFS and OS at 6 months and 1 year. 
• 
To measure PFS in PD-L1 strong population at 6 months and 1 year. 
• 
To measure the duration of clinical benefit using RECIST v1.1 including the different 
response rate between squamous versus non-squamous histological sub-types at 6 
months and 1 year. 
• 
To measure the oesophagitis rates assessed at two months after the last fraction of 
RT has been administered. 
Exploratory 
• 
To evaluate the abscopal effect when pembrolizumab and RT are combined. 
• 
Characterisation of TILs and tumour antigens in the tumour biopsies. These IHC 
analyses will include, but not necessarily be limited to, the following markers: CD4, 
CD8, FOXp3, PD-1, PD-L1, and PD-L2. 
• 
Analysis of research blood samples for ctDNA. 
Summary of Main 
Inclusion Criteria 
• 
Patients ≥18 years of age with measurable (RECIST v1.1) NSCLC; requiring palliative 
RT for which no curative therapy exists will be recruited into the trial. Patients are 
permitted to have extra-thoracic disease which will not be encompassed in the RT 
field. This disease will be assessed for abscopal response. 
• 
ECOG between 0-1 and the ability to tolerate a week or 2.5 week course of palliative 
RT. 
• 
Demonstrate adequate organ function and a baseline lung function of FEV1 > 0.8L 
or > 30%.  
• 
Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumour lesion. 
• 
Female patients of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to confirmation of study eligibility.  
• 
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 6 months after the last dose of study medication. 
Summary of Main 
Exclusion Criteria 
• 
Taking any IMP or using an Investigational device within 4 weeks of the first dose. 
• 
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose. 
• 
Prior monoclonal antibody within 4 weeks prior to the first dose or who has not 
recovered from adverse events due to agents administered more than 4 weeks 
earlier.  
• 
Previous RT to the lung 

 
 
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• 
Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 
weeks prior to the first dose or who has not recovered from adverse events due to a 
previously administered agent. 
• 
Additional malignancy that is progressing or requires active treatment.  
• 
Active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Patients with previously treated brain metastases may participate provided they are 
stable, have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
• 
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.   
• 
Patients with evidence of interstitial lung disease, or history of pneumonitis 
(including non-infectious pneumonitis) that required steroids, or current 
pneumonitis (including non-infectious pneumonitis). 
• 
History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound trial results, interfere with the patient’s participation or is not 
in the best interest of the patient.   
• 
Psychiatric or substance abuse disorders that would interfere with patients 
participation. 
• 
Pregnant / breastfeeding or expecting to conceive within the duration of the trial, 
starting with the screening visit through 6 months after the last dose. 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation 
or checkpoint pathways). 
• 
History of HIV. HIV 1/2 antibodies, Hepatitis B or Hepatitis C. 
• 
Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
Treatment / Main Study 
Procedures 
Patients will be registered to receive pembrolizumab at one of the above dosing levels 
in combination with low or high dose RT. Pembrolizumab will be given 2 weekly at the 
dose level currently under evaluation during RT and then the patient will move into a 
maintenance phase where they will receive 200mg of pembrolizumab alone 3 weekly 
thereafter. Additionally, an expansion phase will take place using the dose administered 
at the achieved MTD. Patients will undergo clinical assessment on the day of each 
administration of pembrolizumab and will continue on this regimen until disease 
progression, unacceptable adverse events, discontinuation of study medication for any 
other reason or withdrawal from the trial. All clinical assessments should be completed 
and reviewed before the administration of the next dose. 
After the end of treatment, each patient will be required to attend a safety follow-up 
visit at 30 days or before the initiation of a new cancer treatment, whichever comes 
first. Patients who discontinue for reasons other than disease progression will be 
followed-up every 9 weeks for disease status until progression, initiating a new anti-
cancer treatment, withdrawing consent, or becoming lost to follow up. Once a patient 
has suffered disease progression or initiated a new cancer treatment they will be 
followed up every 12 weeks to determine their disease status. This will be done by 
reviewing their medical notes and / or contacting the patient or GP directly. Patients will 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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remain on this follow-up until death, withdrawal of consent, or the end of the study 
Additional information on study procedures can be found in the study schedule of 
assessment (Table 3)  
 
 
 
 

 
 
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TABLE OF CONTENTS 
1 
Contact List .................................................................................................................... 2 
2 
Protocol Development Team ........................................................................................ 3 
3 
PROTOCOL SIGNATURES ............................................................................................... 4 
4 
Trial Summary ............................................................................................................... 4 
Primary ...............................................................................................................................5 
Exploratory .........................................................................................................................5 
Primary ...............................................................................................................................6 
• 
To establish the maximum tolerated dose (MTD) that can be safely combined with RT in 
the absence of dose limiting toxicity (DLT)............................................................6 
Exploratory .........................................................................................................................6 
1.0 
BACKGROUND & RATIONALE ..................................................................................... 17 
1.1 
Background.............................................................................................................. 17 
1.1.1 Immune evasion in cancer ...................................................................................17 
1.1.2 Pharmaceutical and Therapeutic Background .....................................................18 
1.1.3 Rationale for combining anti-PD-1 effects with radiation ...................................19 
1.1.4 Preclinical and Clinical Trial Data on Pembrolizumab .........................................20 
1.2 
Rationale for the Trial and Selected Patient Population ....................................... 22 
1.3 
Rationale for Dose Selection/Regimen/Modification ........................................... 24 
1.4 
Rationale for Endpoints .......................................................................................... 25 
1.4.1 Efficacy, Safety and Tolerability Endpoints ..........................................................25 
1.4.2 Progression free survival and overall survival .....................................................25 
1.4.3 Response rates .....................................................................................................26 
1.4.4 Abscopal effect ....................................................................................................27 

 
 
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1.4.5 Biomarker Research .............................................................................................28 
2.0 
Study OBJECTIVES & Endpoints .................................................................................. 28 
2.1 
Study Objectives & Hypothesis .............................................................................. 28 
2.1.1 Primary .................................................................................................................28 
2.1.2 Secondary ............................................................................................................28 
2.1.3 Exploratory ...........................................................................................................29 
2.2 
Study Endpoints ...................................................................................................... 29 
2.2.1 Primary .................................................................................................................29 
1. 
A: To establish the MTD that can be safely combined with RT to the lung in the absence of 
DLT .......................................................................................................................29 
2.2.2 Secondary ............................................................................................................29 
2.2.3 Exploratory ...........................................................................................................29 
3.0 
Study DESIGN .............................................................................................................. 29 
3.1 
Summary of study design ....................................................................................... 29 
3.2 
Treatment Regimen ................................................................................................ 30 
3.2.1 Dose Levels .............................................................................................................. 30 
3.3 
Study Flow chart ..................................................................................................... 32 
3.4 
Follow-Up ................................................................................................................ 32 
3.4.1 30 Days Safety Follow-Up ....................................................................................32 
3.4.2 Post-Safety Follow-Up .........................................................................................32 
3.4.3 Survival Follow-Up ...............................................................................................33 
3.5 
Study Termination .................................................................................................. 33 
3.5.1 Clinical Criteria for Early Trial Termination ..........................................................33 
3.6 
Treatment after Study Termination ....................................................................... 33 
4.0 
Selection of Patients ................................................................................................... 33 

 
 
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4.1 
Screening and Enrolment........................................................................................ 33 
4.2 
Registration ............................................................................................................. 34 
4.3 
Patient Replacement Strategy ................................................................................ 34 
4.4 
Entry Criteria ........................................................................................................... 34 
4.4.1 Inclusion Criteria ..................................................................................................34 
4.4.2 Exclusion Criteria .................................................................................................36 
5.0 
Study Plan and procedures ......................................................................................... 37 
5.1 
Study Schedule ........................................................................................................ 37 
5.2 
Administrative Procedures/Assessments .............................................................. 41 
5.2.1 Informed Consent ................................................................................................41 
5.2.2 Inclusion/Exclusion Criteria .................................................................................42 
5.2.3 Demographic Data, Medical History and Treatment History ..............................42 
5.2.4 Anti-Cancer Therapy Review ...............................................................................42 
5.2.5 Survival Status ......................................................................................................42 
5.2.6 Prior and Concomitant Medications Review .......................................................43 
5.3 
Clinical Procedures/Assessments ........................................................................... 43 
5.3.1 PD-1 Assessment..................................................................................................43 
5.3.2 Adverse Event (AE) Monitoring ...........................................................................43 
5.3.3 Radiation Toxicity Assessment ............................................................................44 
5.3.4 Full Physical Exam ................................................................................................44 
5.3.5 Directed Physical Exam ........................................................................................44 
5.3.6 Vital Signs .............................................................................................................44 
5.3.7 Eastern Cooperative Oncology Group (ECOG) Performance Scale .....................44 
5.3.8 Pulmonary Function Tests ...................................................................................45 
5.3.9 MRC Dyspnea Scale ..............................................................................................45 

 
 
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5.3.10 Pregnancy Tests ...................................................................................................45 
5.3.11 Haematology, Clinical Biochemistry and Urinalysis (including FT3, FT4, TSH, PT, aPTT and β-
hCG†) ...................................................................................................................45 
5.3.12 Pneumonitis Assessment .....................................................................................46 
5.3.13 Tumour Imaging and Assessment of Disease ......................................................46 
5.3.14 Tumour Tissue Collection and Correlative Studies Blood Sampling ....................47 
5.3.15 Tumour Biopsies and Research Blood Samples ...................................................48 
5.3.17 Chain of Custody of Biological Samples ...............................................................50 
5.4 
Total Blood Volume ................................................................................................ 50 
6.0 
Treatments .................................................................................................................. 50 
6.1 
Standard Treatment ................................................................................................ 51 
6.1.1 External Beam radiotherapy – Planning and Treatment .....................................51 
6.1.2 Radiotherapy Dose ..............................................................................................51 
6.1.3 Radiotherapy Assessments and Procedures........................................................51 
6.2 
Trial Treatment - Pembrolizumab .......................................................................... 51 
6.2.4 Packaging and Labelling Information...................................................................53 
6.2.5 Returns and Reconciliation ..................................................................................53 
Upon completion or termination of the study, all unused trial medication will be returned to MSD or 
destroyed at the site per institutional policy. It is the Investigator’s/designees responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept. ....... 54 
6.2.6 Doses and treatment regimens ...........................................................................54 
6.2.7 Timing of Dose Administration ............................................................................54 
6.2.8 Trial Blinding/Masking .........................................................................................55 
6.2.9 Dose Selection/Modification ...............................................................................55 
6.3 
Concomitant medications ....................................................................................... 57 

 
 
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6.3.1 Prohibited Concomitant Medications..................................................................58 
6.3.2 Acceptable Concomitant Medications ................................................................59 
6.4 
Rescue Medications & Supportive Care ................................................................. 59 
6.4.1 Supportive Care Guidelines .................................................................................59 
6.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related 
Events of Clinical Interest (irECI) ............................................................................ 62 
6.6 
Supportive Care Guidelines for Pneumonitis ......................................................... 64 
6.7 
Diet/Activity/Other Considerations ....................................................................... 65 
6.7.1 Diet .......................................................................................................................65 
6.7.2 Contraception ......................................................................................................65 
6.7.3 Use in Pregnancy .................................................................................................66 
6.7.4 Use in Nursing Women ........................................................................................67 
6.7.5 Treatment of Overdose of IMP ............................................................................67 
6.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study67 
6.8.1 Permanent Discontinuation of Trial Medication .................................................67 
6.9 
Withdrawal from the Study .................................................................................... 68 
7.0 
Pharmacovigilance ...................................................................................................... 69 
7.1 
Adverse events ........................................................................................................ 69 
7.1.1 Adverse Event Definition: ....................................................................................69 
7.1.2 Adverse Reaction Definition: ...............................................................................69 
7.1.3 Disease Progression .............................................................................................69 
7.1.4 New Cancers ........................................................................................................69 
7.1.5 Abnormal Laboratory Test Results ......................................................................69 
7.1.6 Pregnancy and Lactation......................................................................................70 
7.2 
Assessing and Recording Adverse Events .............................................................. 70 

 
 
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7.3 
Evaluating Adverse Events ...................................................................................... 70 
7.3.1 Determining AE Severity and Grade ....................................................................71 
7.3.2 Determining AE Causality ....................................................................................71 
7.4 
Serious adverse events (SAEs) ................................................................................ 72 
7.4.1 Reporting SAEs .....................................................................................................72 
7.4.2 Events exempt from being reported as SAEs ......................................................73 
7.4.3 Determining SAE Causality and Expectedness.....................................................73 
7.5 
Events of Clinical Interest ....................................................................................... 74 
7.5.1 Definitions of Evidence of Clinical Interest (ECI) .................................................74 
7.5.2 Reporting of ECIs ..................................................................................................75 
7.6 
Definition of an Overdose for This Protocol and Reporting of Overdose............. 75 
7.7 
Reporting of Pregnancy and Lactation ................................................................... 76 
7.8 
Definition of a Serious Adverse Reaction (SAR)..................................................... 76 
7.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) ...... 76 
7.10 
Reporting of SUSARs ............................................................................................... 76 
7.11 
Annual Reporting of Serious Adverse Events ........................................................ 77 
7.12 
Urgent safety measures .......................................................................................... 77 
8.0 
STATISTICAL ANALYSIS PLAN ...................................................................................... 78 
8.1 
Statistical Analysis Plan Summary .......................................................................... 78 
8.2 
Endpoints ................................................................................................................. 78 
8.2.1 Primary endpoints ...............................................................................................78 
1. 
To establish the MTD that can be safely combined with RT to the lung in the absence of 
DLTs (Part A) ........................................................................................................78 
8.2.2 Secondary endpoints ...........................................................................................79 
8.2.4 Sample Size ..........................................................................................................80 

 
 
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8.2.5 Data analysis ........................................................................................................80 
9.0 
Regulatory, Ethical and Legal Issues ........................................................................... 80 
9.1 
Good Clinical Practice ............................................................................................. 80 
9.2 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB)............. 81 
9.2.1 Initial Approval .....................................................................................................81 
9.2.2 Approval of Amendments ....................................................................................81 
9.2.3 Annual Safety Reports and End of Trial Notification ...........................................81 
9.3 
Regulatory Authority Approval .............................................................................. 81 
9.4 
Notifications of Serious Breaches to GCP and / or the Protocol ........................... 82 
9.5 
Insurance and Liability ............................................................................................ 82 
9.6 
Contact with General Practitioner (GP) ................................................................. 82 
9.7 
Patient Confidentiality ............................................................................................ 82 
9.7.1 Patient Confidentiality and Data Sharing ............................................................82 
9.7.2 Pharmacogenetics Confidentiality .......................................................................83 
9.8 
Data collection and documentation ....................................................................... 83 
9.9 
End of Trial .............................................................................................................. 84 
10.0 
Data and study management ..................................................................................... 84 
10.1 
Source Data ............................................................................................................. 84 
10.2 
Language ................................................................................................................. 84 
10.3 
Data Collection ........................................................................................................ 84 
10.4 
Recording of Data ................................................................................................... 84 
10.5 
Data Management .................................................................................................. 85 
10.6 
Study Management Structure ................................................................................ 85 
10.6.1 Delegations of Responsibilities ............................................................................85 
RM-CTU ............................................................................................................................85 

 
 
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MSD 
86 
Participating Sites ............................................................................................................86 
10.7 
Protocol compliance and amendments ................................................................. 86 
10.8 
Trial Management ................................................................................................... 86 
10.8.1 Trial Management Group (1 per study) ...............................................................87 
10.8.2 Pembrolizumab Project Safety Review Committee (PPSRC) ...............................87 
10.9 
Monitoring .............................................................................................................. 87 
10.10 Quality Control and Quality Assurance .................................................................. 88 
10.11 Clinical study report ................................................................................................ 88 
10.12 Record retention ..................................................................................................... 88 
10.13 Reporting and publication ...................................................................................... 89 
11.0 
REFERENCES................................................................................................................. 90 
12.0 
APPENDICES................................................................................................................. 93 
12.1 
Appendix 1: ............................................................................................................. 93 
12.2 
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) .... 93 
12.3 
Appendix 3: LENT SOMA Scales for all Anatomical Sites....................................... 94 
12.4 
Appendix 4: Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumours .................................................................. 94 
12.5 
Appendix 5: Identification, Evaluation and Management of irECIs. ..................... 94 
12.6 
Appendix 6: MRC Dyspnea Scale ............................................................................ 99 
 
 

 
 
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1.0 
BACKGROUND & RATIONALE 
1.1 
Background 
1.1.1 
Immune evasion in cancer 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known 
for many years (1).  Accumulating evidence shows a correlation between tumour-infiltrating lymphocytes (TILs) in 
cancer tissue and favourable prognosis in various malignancies (2-6).  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. 
In order to effectively evade the immune system, tumours can employ a variety of mechanisms. An initial 
immunogenic response to tumour cells can occur through the innate immune system for example through natural 
killer (NK) cell mediated lysis. NSCLC can evade such an attack through down regulation of NK ligands, such as NKG2D 
or avoid Fas-induced apoptosis (7, 8). The immune system may then develop an adaptive immune response requiring 
competent cytotoxic T cells. This is mediated through the major histocompatibility complex (MHC) system. Antigen 
presenting cells (APC) capture tumour antigens priming them to T cells in regional lymph nodes. NSCLC display 
reduced MHC class 1 expression therefore evading the adaptive immune response. After priming, T cells are released 
into the circulation and migrate to tumour tissue where they find tumour specific antigens and differentiate into 
effector T cells. This process relies on signals from the T cell receptor and several co-stimulatory and co-inhibitory 
molecules. However many tumours are able to induce T cell anergy. This has been effectively demonstrated in NSCLC 
that induce aberrant expansion of CD4+ FoxP3+ regulatory T cells, thus inhibiting cytotoxic T cell and NK cell activity 
(9). 
 
The immune checkpoint pathway in T cell responses and under normal conditions through complex processes 
regulates effector T cell response. Among the components of this pathway are cytotoxic T-lymphocyte antigen-4 
(CTLA-4) which is expressed on the cell surface of a cytotoxic T cell once it becomes active allowing binding with B7-1 
and B7-2 on the APC keeping cytotoxic activity in check (10).  
Another key component of this pathway is the PD-1/PD-L1 immune checkpoint pathway. 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 (10).   

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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1.1.2 Pharmaceutical and Therapeutic Background 
PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4 and 
has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) (7, 8).  The structure of murine PD-1 has been resolved (11).  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 signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling 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 signaling cascade (7, 12-14). 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 signaling proteins (15, 16).  PD-1 is expressed on activated lymphocytes including peripheral CD4+ 
and CD8+ T cells, B-cells, T regs and NK cells (17, 18).  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T cells, as well as subsets of macrophages and dendritic cells (18).  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-
haematopoietic tissues, as well as in various tumours (15, 19-21).  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 signaling 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-haematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on APCs 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 (15).  Although healthy organs express little (if 
any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T cell inhibitor.  Abnormal 
expression PD-L1 is identified in 19% to 100% of NSCLC tumours, depending in part on the antibody, histology, and 
technique reported (22-25) although the figure is more likely to around the 50% mark (23, 26). Some groups have 
noted that PD-L1 expression seems to be more commonly observed in sarcomatoid and adenocarcinoma subtypes of 
lung cancer, and it has been associated with poor prognosis (22, 23). TILs seem to be absent in PD-L1 positive regions 
of tumours (23). High PD-L1 positive frequencies have also been seen in head and neck, cervical (29%), glioblastoma 
multiforme (25%), bladder (21%) and oesophageal cancer (20%). Within oesophageal cancer, PD-L1 expression is 
higher in the squamous population compared to other histologies (27). 
 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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PD-L1 expression may be directly regulated by STAT-3 and appears to be further stimulated by immunosuppressive 
cytokines, such as IL-27. 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 (10). 
 
1.1.3 
Rationale for combining anti-PD-1 effects with radiation 
The role of T cells in response to radiation was suggested in 1979 when reduced therapeutic efficacy was noted in 
mice that lacked an adequate T cell response (28). Now it is known that ionising radiation (IR) induced cell death can 
generate tumour cell antigens for dendritic cell presentation. IR in fact can generate immunogenic cell death perhaps 
more effectively than chemotherapy. The 3 steps required in this process include cell surface translocation of 
calreticulin, the extracellular release of high-mobility group protein B1 (HMGB1) a non-histone nuclear protein, and 
release of ATP. Tumour cells that receive sub-lethal doses of radiation undergo phenotypic changes that enhance 
their susceptibility to immune effectors (29-31). Enhanced expression of death receptors (32, 33), MHC class 1 
molecules (29, 34, 35), co-stimulatory molecules (36), adhesion molecules (37-39), and stress-induced ligands (40-42) 
on tumour cells exposed to radiation increased their recognition and killing by T cells in vitro and/or in vivo in several 
cancer models. 
Theoretically if combined with the ideal immunotherapeutic agent RT can engage both the innate and adaptive arms 
of the immune system, with the potential to convert the irradiated cancer into an in situ vaccine that elicits tumour-
specific T cells. Preclinical studies have demonstrated this in several tumour types with a variety of 
immunotherapeutic agents including Flt3 ligand, CpG, anti-CTLA-4, anti-CD137 with anti-PD-1 and viral therapies. The 
majority of studies demonstrate release of tumour antigen leading to the induction of anti-tumour T cell effect, while 
other studies demonstrate up regulation of MHC class I on tumour cells. One study examined mice bearing 
established orthotopic AT-3 mammary tumours and strikingly all mice treated with anti-CD137 and anti-PD-1 
combined with single- or low-dose fractionated RT were cured. CD8+ T cells were essential for curative responses to 
this combinatorial regimen. CD137 expression on tumour-associated CD8+ T cells was largely restricted to a subset 
that highly expressed PD-1. PD-1 signaling within the AT-3 tumours was a critical limiting factor to the therapeutic 
efficacy of anti-CD137 therapy, alone and in combination with RT (43).   
Recently with the advent of large radiation fraction sizes in the form of stereotactic body radiotherapy (SBRT), the 
concept of combining SBRT with immune check point inhibitors has been explored with some groups suggesting that 
combined modality treatment with SBRT may be more efficacious than low dose RT. In a mouse orthotropic cell line 
glioma model, SBRT with 10Gy was tested in combination with anti-PD-1 antibodies. Anti-PD-1 antibodies led to long 
term cures in a subset of mice, which was not seen with either treatment modality alone (44). Post treatment analysis 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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of brain tissue showed increased cytotoxic T cells in the combined modality arm and decreased regulatory T cells. 
However the interaction between dose and immune effect is far more complex. Verbrugge et al demonstrated this 
complex interaction by irradiating B16-OVA murine with melanoma with up to 15Gy, given in various size fraction. For 
single fractions, tumour control and number of tumour-specific T cells were radiation dose dependent. However, at 
the highest dose, there was also an increase in regulatory T cells, which tend to down regulate the immune response. 
Fractionated irradiation at 7.5Gy/fraction seemed to produce the best tumour control and tumour specific T cell 
response while still maintaining low regulatory T cell numbers (43). A further study supports fractionating radiation 
treatment in conjunction with immunotherapy, by testing anti-CTLA-4 antibodies with radiation in a mouse breast 
cancer model. Mice were treated with 20Gy × 1, 8Gy × 3, or 6Gy × 5 fractions in combination with monoclonal 
antibody against CTLA-4. Authors found that fractionated but not single-dose RT induces an abscopal effect when 
used with anti-CTLA-4 antibody (45). However, another preclinical study comparing ablative radiation doses against 
fractionated radiation noted that ablative radiation, such as a single dose of 20–25Gy, dramatically increased T cell 
activity and tumour control. When 5Gy × 4 fractions given over 2 weeks were compared against a single 20Gy dose, 
radiation-initiated immune responses and tumour reduction appeared to be abrogated by the fractionated radiation 
(46). As is evident the relationship between RT dose, fraction size and immune interplay is a complex one. This study 
therefore in part will begin to explore the effects of dose fractionation on T cell response in the clinical setting. This 
will aid design of future RT trials help determine if conventionally fractionated RT provides the ideal tumour micro-
environment for anti-PD-1 therapy or if combination with SBRT should be explored in concept. However prior to 
designing such trials the tolerability and safety of drug with IR needs to be established which is the primary objective 
of this trial. 
1.1.4 
Preclinical and Clinical Trial Data on Pembrolizumab 
1.1.4.1 Clinical trial data on Pembrolizumab 
At ASCO 2015, pooled results from KEYNOTE-001 were presented. 495 patients with NSCLC showed an objective 
response rate as assessed by RECIST v1.1 of 19.4% (95% confidence interval 16.0 – 23.2), which included a response 
rate of 18.0% (95% confidence interval 14.4 – 22.2) in the 394 treatment naïve patients and 24.8% (95% confidence 
interval 16.7 – 34.3) in the 101 previously treated patients. The response rates were similar regardless of dose, 
schedule, and histological diagnosis. The median duration of response of 12.5 months (range 1.0 – 23.3) in all 
patients, 23.3 months (range 1.0 – 23.3) in treatment naïve patients and 10.4 months (range 1.0 – 10.4) in previously 
treated patients. The median PFS was 3.7 months (95%CI: 2.9 – 4.1) for all patients, with 6.0 months (95%CI: 4.1 – 
8.6) in treatment naïve patients and 3.0 months (95%CI: 2.2 – 4.0) in previously treated patients. The median OS was 
12.0 months (95%CI: 9.3 – 14.7) for all patients, with 16.2 months (95%CI: 16.2 – not reached) in treatment naïve 
patients and 9.3 months (95%CI: 8.4 – 12.4) in previously treated patients (47).   

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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Treatment related adverse events (AEs) occurred in 351 patients (70.9%), with no clear difference according to dose 
or schedule. The most common AEs attributed to pembrolizumab were fatigue (any grade: 19.4%; grade 3 – 5: 0.8%), 
pruritus (any grade: 10.7; grade 3 – 5: 0%), and decreased appetite (any grade: 10.5%; grade 3 – 5: 1.0%), with no 
clear difference according to dose or schedule. AEs of grade 3 or higher were reported in 47 of 495 patients (9.5%). 
The only treatment-related AEs of an inflammatory or immune-mediated nature that occurred in more than 2% of 
patients were infusion related reactions (in 15 patients [3%]), hypothyroidism (in 34 patients [6.9%]), and 
pneumonitis (in 18 patients [3.6%]). All patients with hypothyroidism were successfully treated with medical therapy. 
Pneumonitis of grade 3 or greater was observed in 9 patients (1.8%), including 1 (0.2%) who died. At the time of data 
analysis, 2 cases of pneumonitis (both grade 1 or 2) were on going (47).  
 
 This data has resulted in pembrolizumab being granted breakthrough therapy designation with the FDA for patients 
with NSCLC whose cancers have progressed on or after platinum-containing chemotherapy, as well as targeted 
agents in those with EGFR mutations and ALK gene rearrangements (47). Actively recruiting studies include KEYNOTE-
024, is a phase III randomised controlled trial looking at pembrolizumab in first line NSCLC (48), and KEYNOTE-021, a 
phase 1 study looking at the combination of ipilimumab and pembrolizumab (49). 
 
KEYNOTE-001 also validated the PD-L1 biomarker using the anti-PD-L1 antibody clone 22C3 (Merck) and 
immunohistochemistry. Tumour slides were stained and scored for neoplastic membranous staining and intercalated 
mononuclear inflammatory cells, as with <1%, 1-49%, or >50%. Using receiver operatory characteristic curve analysis 
they found that a PD-L1 score of >50% (strong) was the best predictor of efficacy of pembrolizumab, with a response 
rate of 45.2% (95%CI: 33.5 – 57.3) and a median PFS of 6.3 months. The media OS has not yet been reached. The 
response rates in patients who scored PD-L1 1-49% was 16.5% (95%CI: 9.9 – 25.1) and in those who scored PD-L1 <1% 
was 10.7% (95%CI: 2.3 – 28.2) (47).  
 
Similarly in melanoma, he immunotherapeutic effect of pembrolizumab is now established. The phase I study 
presented at ASCO 2014 consisted of 411 patients with advanced melanoma on pembrolizumab yielded long-term 
responses in a high percentage of patients. One-year overall survival was 69% across all patient subgroups, and 
responses were on going in 88% of patients at analysis, after a median follow-up of 12 months. The study enrolled 
221 patients with prior ipilimumab treatment and 190 patients who had not previously received ipilimumab. Overall, 
34% of patients experienced tumour response, as assessed by Independent Review Committee, including 40% of 
patients not previously treated with ipilimumab and 28 % of patients whose disease progressed on prior ipilimumab. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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Responses were durable with 88% on going at the time of analysis. Activity was observed across all dose levels and 
patient subgroups, irrespective of prior ipilimumab therapy, performance status, LDH levels, BRAF mutation status, 
tumour stage, and number and type of prior therapies. Daud et al presented biomarker data for 135 of these patients 
at the American Association for Cancer Research 2 months prior to the ASCO presentation. Tumour PD-L1 expression 
was assessed by IHC. A preliminary cut-off of 1% of stained cells was used to define PD-L1 Median PFS was 36 weeks, 
6-month OS rate was 89%, and 12-month OS rate was 81%. Median duration of response and OS were not reached. In 
the 116 patients with measurable disease, ORR was 41%. PFS and response rate were significantly associated with 
tumour PD-L1 expression. Median PFS for PD-L1 positive tumours was 10.6 months versus 2.9 months for PD-L1 
negative patients (HR 0.54, P-value=0.034). The drug has been granted FDA priority review designation under its 
accelerated Approval program. 
 
1.1.4.2 Preclinical data on Pembrolizumab 
Preclinical data for anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumour responses as a 
monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma and colorectal carcinoma. 
Blockade of the PD-1 pathway effectively promoted CD8+ T cell infiltration into the tumour and the presence of IFN-γ, 
granzyme B and perforin, indicating that the mechanism of action involved local infiltration and activation of effector 
T cell function in vivo (30-36). Experiments have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as 
well as in combination with chemotherapy in syngeneic mouse tumour models (see the Investigator’s Brochure [IB]). 
 
Pembrolizumab (trade name Keytruda®, previously known as MK3475/SCH 900475) is a potent and highly selective 
humanised 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.   
1.2 
Rationale for the Trial and Selected Patient Population 
There is an increasing body of evidence of the efficacy of anti-PD-1 therapy in several tumour types notably 
melanoma and lung cancer, both of which highly express tumour PD-L1. Biomarker data suggests that tumours 
expressing PD-L1 will be particularly susceptible to pembrolizumab. This drug is therefore being explored in a number 
of phase II and phase III trials in differing tumour types known to express PD-L1. In addition a phase 1 trial is assessing 
pembrolizumab activity in PD-L1 positive patients with advanced cancers in 20 solid tumour types not previously 
assessed. Pembrolizumab-0028 is a multicentre non-randomised, trial recruiting patients with colon/rectal 
adenocarcinoma, anal canal squamous cell carcinoma, pancreas adenocarcinoma, oesophageal squamous cell 
carcinoma/adenocarcinoma, biliary tract adenocarcinoma, carcinoid tumours, neuroendocrine carcinomas, ER 
positive Her2 negative breast cancer, ovarian epithelial, fallopian tube or primary peritoneal carcinoma, endometrial 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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carcinoma, cervical squamous cell cancer, vulvar squamous cell carcinoma, small cell lung cancer, mesothelioma, 
head and neck tumours,  glioblastoma multiforme, leiomyosarcoma, and prostate adenocarcinoma. This trial 
prohibits radiation prior to trial entry and during trial participation. Similarly other on-going trials with 
pembrolizumab have prohibited concomitant radiation. This is due to two reasons; firstly to maintain the scientific 
integrity of the trials but secondly due to lack of knowledge of the effects of pembrolizumab on radiation and its 
radiosensitising potential.  
A reported adverse event (AE) of this class of drug is pneumonitis. Table 1 describes the incidence of pneumonitis in 
the melanoma patients. Pneumonitis/interstitial lung disease was observed in 1.9% of patients treated with 2 mg/kg 
Q2W, 1.6% of patients treated with 10 mg/kg Q3W, and 10.5% of patients treated with 10 mg/kg Q2W. The incidence 
seems similar in patients treated at the every 3 week schedule, but is more prevalent in patients treated at the every 
2 week schedule. These cases are grade 1-2 in severity. Most cases are considered drug-related by investigators. No 
drug-related deaths have resulted from pneumonitis; however a 96-year old man with melanoma suffered a fatal 
myocardial infarction after a bronchoscopy to evaluate grade 2 interstitial lung disease. 
 
 
PEMBROLIZUMAB  
2 mg/kg 
Q3W 
PEMBROLIZUMAB  
10 mg/kg 
Q3W 
PEMBROLIZUMAB  
10 mg/kg 
Q2W 
Total 
n 
% 
n 
% 
n 
% 
n 
% 
Patients in population 
162 
- 
192 
- 
57 
- 
 
411 
Respiratory thoracic 
mediastinal disorders 
3 
1.9 
3 
1.6 
6 
10.5 
12 
2.9 
Interstitial lung disease 
0 
0 
0 
0 
1 
1.8 
1 
0.2 
Pneumonitis 
3 
1.9 
3 
1.6 
5 
8.8 
11 
2.7 
Table 1: Patients with Pneumonitis (Incidence > 0%) in One or More Treatment Groups for melanoma patients 
From the 38 patients with previously-treated NSCLC treated with Pembrolizumab 10 mg/kg every 3 weeks, 2 patients 
(5.3%) have been reported with pneumonitis and one patient (2.6%) has been reported with steroid-responsive 
pulmonary oedema. Two cases were grade 2; the case of pulmonary oedema was grade 3. These cases began as early 
as four days after the first dose to several cycles (Week 18) after the first dose. It is not clear the role of prior thoracic 
radiation to the development of this adverse event. The grade 3 episode responded to steroids, whereas the grade 2 
cases did not. The grade 3 pulmonary oedema and a case of grade 2 pneumonitis were considered drug-related; the 
third case was considered not drug-related. All three patients died from malignant neoplasm progression. In the case 
of the two drug-related cases, the patients died within 3 weeks of the start of pneumonitis or pulmonary oedema 
from malignant neoplasm progression 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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This study has been designed to assess that pembrolizumab can be safely administered in patients receiving palliative 
courses of RT to the lung. Patients with NSCLC are eligible for the study. If this is proven, patients receiving 
pembrolizumab in the future as long term therapy will not require treatment interruptions whilst receiving palliative 
RT to the lung. Secondly the trial will explore dose scheduling. This will help design future studies looking at 
concomitant pembrolizumab and RT and help establish whether conventionally fractionated RT or SBRT protocols 
should be considered. It is not a prerequisite of the study to be PD-L1 strong since the main objective of the study is 
to assess safety. However biomarker data will be collected and exploratory analyses will be performed to assess if PD-
L1 status influences drug-RT responses.  
1.3 
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (KEYNOTE-001) was conducted to evaluate the safety and clinical activity of single agent 
Pembrolizumab.  The dose escalation portion of this trial evaluated three dose levels, 1mg/kg, 3mg/kg, and 10mg/kg, 
administered every 2 weeks (Q2W) in patients with advanced solid tumours.  All 3 dose levels were well tolerated and 
no DLTs 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 (1mg/kg, 3mg/kg and 10mg/kg Q2W).  No MTD was 
been identified, with 10 mg/kg Q2W being the highest dose tested.  Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
Pharmacokinetic data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release assay) suggested 
that peripheral target engagement is durable (>21 days).  This early pharmacokinetic and pharmacodynamic data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data from 476 patients. 
Within the resulting population pharmacokinetic model, clearance and volume parameters of pembrolizumab were 
found to be dependent on body weight. The relationship between clearance and body weight, with an allometric 
exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalised 
dosing or a fixed dose across all body weights.  Pembrolizumab has been found to have a wide therapeutic range 
based on the melanoma indication.  The differences in exposure for a 200mg fixed dose regimen relative to a 2mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 
for pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10mg/kg Q3W vs the proposed dose regimen of 2mg/kg Q3W (i.e. 5-fold higher dose and 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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exposure). The population pharmacokinetic evaluation revealed that there was no significant impact of tumour 
burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
 
For this study maintenance treatment will be given as 200mg Q3W. Dosing during RT is given on a Q2W schedule to 
maximise the radiosensitising potential. The starting dose (dose level 1) will be 100mg Q2W, decreasing to dose level 
-1 i.e. 50mg Q2W, if MTD in dose level 1 is achieved. Dose level 2 is 200mg Q2W. Pneumonitis levels were >10% for 
monotherapy in melanoma patients at dose level 10mg/kg Q3W but for this study only 3 doses at dose level 2 will be 
given concomitant with RT followed by the maintenance dose of 200mg Q3W. Dose level 2 is expected to be the 
MTD. In the expansion cohort the dose of pembrolizumab administered with RT will be the MTD dose.  
 
1.4 
Rationale for Endpoints 
1.4.1 
Efficacy, Safety and Tolerability Endpoints 
The primary objective of this study is to determine the safety and tolerability of combining pembrolizumab with RT. 
For this objective there will be 1 condition that will be regarded as DLT, and 2 conditions that will be criteria for the 
termination of the study. For this study a DLT would be regarded as any event of pneumonitis at ≥ grade 2.   
• 
Pneumonitis: 
o Pneumonitis rates for palliative RT to the lung are consistently below 10%. It has been shown for high 
dose pembrolizumab pneumonitis rates can go up to 10%. As this study is combining these two 
treatments pneumonitis of ≥ grade 2 will be considered a DLT. A 25% rate of ≥ grade 2 pneumonitis 
or more will be considered unacceptable. 
In addition, if 1 patient with oesophagitis of ≥ grade 4 or 2 patients of myelitis of ≥ grade 2 occurred at dose levels -1 
and/or 1 these would be considered events on which the study would be terminated. However, if these adverse 
events occurred at dose levels 2 and/or 3, they would lead to dose de-escalation and cohort expansion as defined in 
Section 3.2.1 of the protocol.  
Tolerability will be assessed by documenting all AEs and serious adverse events (SAEs). This is part of the safety 
endpoint to ensure that the combination regimen is tolerable and that there are no unexpected AEs when combining 
pembrolizumab with RT. Events of clinical interest (ECI) as per Table 13 will also be assessed. 
1.4.2 
Progression free survival and overall survival  
Median OS for lung tumours is <12 months and median PFS < 6months in patients receiving low dose RT. It is 
anticipated that with the addition of pembrolizumab during the RT period and continuation of the drug into the 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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maintenance phase, PFS and OS will be potentially prolonged. With the duration of PFS and OS being significantly 
more prolonged in PD-L1 strong patients. 
1.4.3 
Response rates 
Response rates will be assessed locally at site using RECIST v1.1 (50) that will be adapted to account for the unique 
tumour response characteristics seen with treatment of pembrolizumab. Immunotherapeutic agents such as 
pembrolizumab may produce anti-tumour effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course of responses seen 
with cytotoxic agents, and can manifest a clinical response after an initial increase in tumour burden or even the 
appearance of new lesions. Therefore, standard RECIST v1.1 may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. 
 
Therefore, RECIST v1.1 will be used with the following adaptations: 
• 
If radiologic imaging shows initial progressive disease (PD), tumour assessment should be repeated ≥4 weeks 
later in order to confirm PD with the option of continuing treatment while awaiting radiologic confirmation of 
progression.  
o Patients may continue treatment while waiting for confirmation of PD if they are clinically stable as 
defined by the following criteria: 
▪ 
Absence of signs and symptoms indicating disease progression. 
▪ 
No decline in ECOG performance status. 
▪ 
Absence of rapid progression of disease. 
▪ 
Absence of progressive tumour at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention. When feasible, patients should not be discontinued 
until progression is confirmed. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some patients can have a transient 
tumour flare in the first few months after the start of immunotherapy, but with subsequent 
disease response. Patients that are deemed clinically unstable are not required to have 
repeat imaging for confirmation of progressive disease. 
• 
If repeat imaging shows a reduction in the tumour burden compared to the initial scan demonstrating PD, 
treatment may be continued /resumed.  
 
• 
If repeat imaging confirms PD, patients will be discontinued from study therapy.  
o NOTE: If a patient with confirmed radiographic progression (i.e. 2 scans at least 28 days apart 
demonstrating PD) is clinically stable or clinically improved, and there is no further increase in the 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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tumour dimensions at the confirmatory scan, an exception may be considered to continue treatment 
upon consultation with the Sponsor.  
Clinically stable patients should also have at the confirmatory scan no further increase in the target 
lesions, no unequivocal increase in non-target lesions, and no additional new lesions develop (non-
worsening PD) to continue study treatment. 
 
In determining whether or not the tumour burden has increased or decreased, investigators should consider all target 
lesions as well as non-target lesions. Differential response rates will be assessed for tumours that are squamous 
versus non-squamous histological subtypes. RECIST v1.1 states that tumour lesions must be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be recorded).  
 
In patients who have initial evidence of radiological PD, it is at the discretion of the treating physician whether to 
continue a patient on study treatment until repeat imaging is obtained a minimum of 4 weeks later. This clinical 
judgment decision should be based on the patient’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. The details of the clinical decision must be recorded in full in the patients’ medical 
notes. 
 
1.4.4 
Abscopal effect 
The abscopal effect refers to a rare phenomenon of tumour regression at a site distant from the primary site of RT 
(51). Localised RT has been shown to induce abscopal effects in several types of cancer, including melanoma, 
lymphoma, renal-cell carcinoma and NSCLC (52-55). The effect is attributed to activation of the systemic immune 
response. Radiation-induced inflammation is known to increase antigen presentation, subsequent tumour 
recognition, and can ultimately, enhance the tumour-directed immune response (56). This effect may be more 
pronounced in response to ablative rather than conventional dosage or fractionation schedules (46). More recently, 
the abscopal effect has been described in the context of patients receiving immunotherapy concurrently with RT. 
Formenti et al described a case of abscopal response in a patient with advanced NSCLC who received palliative 
hepatic RT while on ipilimumab. The response was seen 2.5 months following RT (57). Experimental data from 
multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects 
of IR are recognised as contributing to systemic antitumor immunity. Therefore, the traditional palliative role of RT in 
metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to 
the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even 
among metastatic and heavily pre-treated cancer patients (58). 

 
 
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For this study this phenomenon can only be assessed in those patients who have disease present outside of the 
irradiated field and will be an exploratory analysis only. For patients with assessable disease outside the RT field; 
individual lesion response (Completed Response [CR]/ Partial Response [PR]/ PD/ Stable disease [SD]) will be 
determined by RECIST v1.1. 
1.4.5 
Biomarker Research 
Archived tissue, newly collected biopsies and correlative blood studies will be assessed for characterisation of TILs 
and tumour antigens. However any archived slides used must have been generated within 6 months prior to assay 
due to sample stability limitations. Blood samples will be obtained before the first dose of pembrolizumab (week 0), 
then again at week 4, at cycle 2 and on disease progression for the analysis of ctDNA, but not necessarily limited to 
this. 
This tumour analysis will allow assessment for PD-L1 status, which could in turn be used to assess differential 
responses rates according to PD-L1 status. This trial will not be enriched for PD-L1 strong patients, however PD-L1 
testing will be batched and performed retrospectively. Furthermore, it will assess for possible effects of immune 
priming with RT. 
2.0 
STUDY OBJECTIVES & ENDPOINTS 
2.1 
Study Objectives & Hypothesis 
2.1.1   Primary 
Objective: To determine the safety and tolerability of pembrolizumab in combination with RT to the lung. 
Hypothesis: Pembrolizumab can be safely administered in combination with both high and low dose RT to the lung. 
Objective: To describe the safety profile of pembrolizumab in combination with RT to the lung.  
Hypothesis: Pembrolizumab can be safely administered in combination with RT to the lung.  
2.1.2 
Secondary 
Objective: To assess overall PFS and OS. 
Hypothesis: Combining pembrolizumab with RT and with maintenance treatment leads to prolonged responses 
following palliative RT. 
Objective: To evaluate PFS against PD-L1 expression. 
Hypothesis: Prolonged responses following palliative RT are expected in patients with greater in PD-L1 expression. 
Objective: To assess overall responses rates as per RECIST v1.1 and differential responses rates in squamous versus 
non-squamous histological subtypes. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 29 of 
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Hypothesis: High levels of PD-L1 expression predict for poor prognosis in squamous carcinoma. 
Objective: To assess oesophagitis rates in this population 
Hypothesis: Pembrolizumab can be safely administered in combination with RT for lung irradiation. 
 
2.1.3 
Exploratory 
Objective: To assess for evidence of abscopal response by individual lesion response (CR/PR/PD/SD) determined by 
RECIST v1.1. 
Hypothesis: Combination RT with pembrolizumab leads to abscopal responses 
Objective: Identification of biomarkers that correlate with immunological response to therapy 
 
2.2 
Study Endpoints 
2.2.1 
Primary 
1. 
A: To establish the MTD that can be safely combined with RT to the lung in the absence of DLT 
B: To measure the toxicity rate of DLTs assessed two months after the last fraction of RT has been administered 
2.2.2 
Secondary 
1. 
To measure the PFS and OS at 6 months and 1 year. 
2. 
To measure PFS and OS in PD-L1 strong population at 6 months and 1 year.  
3. 
To measure the duration of clinical benefit using RECIST v1.1 including the different response rates between 
squamous and non-squamous histological sub-types at 6 months and 1 year. 
4. To measure the oesophagitis rates assessed at two months after the last fraction of RT has been 
administered.  
 
2.2.3 
Exploratory  
1. 
To evaluate the abscopal effect between pembrolizumab and RT. 
2. 
Characterisation of TILs and tumour antigens in the tumour biopsies. These IHC analyses will include, but not 
necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. 
3. 
Analysis of research blood samples for ctDNA. 
 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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3.0 
STUDY DESIGN 
3.1 
Summary of study design 
This is a single centre non-randomised phase 1b open label trial of pembrolizumab given in combination with RT and 
will recruit up to 36 patients with lung cancer undergoing palliative RT to the lung. The study will be conducted in two 
parts; initially as a dose escalation trial (Part A), followed by an expansion stage (Part B) wherein patients will be 
treated at the administered dose below the achieved MTD. Patients will be allocated to either low or high dose RT as 
standard of care and will be registered to receive pembrolizumab, in combination with their treatment. Patients will 
continue on the treatment regimen described in the study flow chart (section 3.3) unless they have PD, unacceptable 
toxicities, discontinuation for other reasons or withdrawal from the study. 
 
3.2 
Treatment Regimen 
Each patient will receive either high or low dose external beam RT as per standard protocol (Appendix 1). All patients 
will commence with a pre-loading dose of pembrolizumab (at the dose level under current evaluation –100/200mg) 
administered 14 days prior to RT (week 0), another dose at day 1 of RT (week 2) and then for high dose patients only 
another dose 14 days after the commencement of RT (week 4). Both the low dose and high dose RT arms will run 
simultaneously. Two weeks after the completion of RT; if the patient is to continue on treatment they will enter the 
maintenance phase and will receive 200mg of pembrolizumab alone every 3 weeks until PD, unacceptable toxicities, 
discontinuation for other reasons or withdrawal from the study. Patients receiving low dose RT with begin this phase 
on week 5 and patients receiving high dose RT will begin on week 6. 
 
A minimum of 3 patients will be required per RT cohort at each dose level. A minimum gap of 1 week should be left 
between the treatment of the first and second patient with the combination of RT and pembrolizumab during the 
dose escalation phase to mitigate against multiple patients suffering from any acute toxicity. The second and third 
patient need to be started at least 24 hours apart during the dose escalation phase.  If no DLTs are observed in the 
first 3 patients at a dose level, pembrolizumab will be escalated to the next dosing level. If 1 in 3 patients experience 
a DLT then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT then the dose will be 
escalated to the next dosing level. However, if ≥ 2 in 6 patients experience a DLT then the maximum administered 
dose (MAD) will have been reached and the previous dosing level, the MTD, should be used for the expansion phase. 
If the MAD is reached at dose level 1 the study will de-escalate to dose level -1. If the MTD is seen at dose level -1 in 
both arms then the study will be stopped. Once the MTD has been determined the trial enters the expansion cohort 
whereby a further 12 patients are treated with the determined dosage of pembrolizumab in combination with high 
dose RT only (see section 3.2.1).   

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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3.2.1 Dose Levels 
The rate of entry and escalation to the next dose level will depend upon assessment of the toxicity profile of patients 
entered at the previous level. The DLT will be for a period of 2 months following the final fraction of RT (at the 
beginning of cycle 4; see Table 3), using Common Terminology Criteria for Adverse Events (CTCAE) v4.0 for acute 
toxicity by the Pembrolizumab Project Safety Review Committee (PPSRC) before recruitment to the next dose level 
can begin. 
 
For this study DLTs will be assessed by the presence of pneumonitis of ≥ grade 2. Pneumonitis will be assessed at 
screening, start of RT (week 2) and cycle 1, 2 and 3 of the maintenance phase.  At these visits all patients must be 
assessed on the basis of clinical symptoms combined with findings from previous CXR and CT scans. Dose escalation 
to the next dose level will not proceed until the following criteria are satisfied: 
• 
If 0/3 patients experience a DLT escalation to the next dose level can proceed. 
• 
If 1/3 patients experiences a DLT a further 3 patients will be assessed at that dose level. 
o If 1/6 patients experience a DLT pneumonitis then escalation to the next dose level can proceed.   
o If ≥ 2/6 patients in a specific dose level experience a DLT, the MAD will have been reached and all 
patients in the expansion cohort will be recruited at the previous dose level, the MTD. 
• 
If 2/3 patients experience a DLT then the MAD will have been reached and the expansion cohort phase will 
begin at the previous dose level, the MTD, unless this occurs at dose level 1 wherein the study will de-
escalate to dose level -1.  
• 
If the MTD occurs at dose level -1 the expansion cohort will go ahead at dose level -1. 
 
All dose escalation and stopping rules used will be identical in both the low dose and high dose cohorts, respectively. 
However, the low and high dose RT arms are independent of each other running in parallel, the outcome from one is 
not expected to affect the decision-making process in the other. Dose expansion will be in the high dose RT arm, as 
the clinical data reviewed here supports a higher dose being more immunogenic. However, the dose per fraction is 
higher in the low dose RT arm (4Gy/fraction) versus high dose RT arm (3Gy/fraction), and therefore the response 
rates during the dose escalation phase will have to be carefully considered by the PPSRC before confirming dose 
expansion.  If in the event the high dose RT arm proves to be too toxic during dose escalation i.e. 2 or more DLTs in 
dose level -1, the dose expansion will occur, at the MTD defined, in the low dose RT arm only assuming it has not 
occurred at dose level -1 too.  
 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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3.3 
Study Flow chart 
Low dose radiotherapy group  
 
 
 
 
 
 
 
 
 
 
High dose radiotherapy group 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiotherapy phase 
 
 
Maintenance 
phase 
 
 
Maintenance  
phase 
 
 
Radiotherapy 
phase 
0 
2 
4 
6 
8 
10 
12 
14 
Time (weeks) 
Pembrolizumab  
continues every 3 weeks 
Cycle 
1 
Cycle 
2 
Cycle 
3 
0 
2 
4 
6 
8 
10 
12 
14 
Time (weeks) 
Pembrolizumab  
continues every 3 weeks 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Radiotherapy administration  
Maintenance dose of Pembrolizumab  
Cycle 
4 
Radiotherapy dose of Pembrolizumab  
 
3.4 
Follow-Up 
3.4.1 
30 Days Safety Follow-Up 
All Patients will be required to attend a safety follow-up visit 30 days after the last dose of pembrolizumab or before 
the initiation of a new anti-cancer treatment, whichever comes first. All AEs and SAEs that occur prior to the safety 
follow-up visit should be reported as described in section 7.  After the safety follow-up, 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 CRF.  
 
3.4.2 
Post-Safety Follow-Up 
Patients who discontinue trial treatment for any reason other than disease progression will move into the follow-up 
phase and should be assessed every 9 weeks (63 ± 7 days) and by radiologic imaging as per standard of care to 
monitor disease status.  Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, PD, death, withdrawal or end of the study.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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3.4.3 
Survival Follow-Up 
Once a patient experiences confirmed PD or starts a new anti-cancer therapy, the patient moves into the survival 
follow-up phase and will be followed up every 12 weeks to determine their disease status. This will be done by 
reviewing their medical notes and/or contacting the patient and/or General Practitioner directly. Patients will remain 
on this follow-up until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
3.5 
Study Termination 
The end of the study is defined when the last patient has completed or discontinued the study for other reasons. 
3.5.1 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete. 
2. Poor adherence to protocol and regulatory requirements. 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to 
patients. 
4. Plans to modify or discontinue the development of the study drug. 
5. If MTD is seen at dose level -1. 
6. If the incidence of ≥ grade 2 pneumonitis is ≥25% in the study. 
7. The occurrence of 1 patient with oesophagitis ≥ grade 4, at dose levels -1 and/or 1. 
8. The occurrence of 2 patients with myelitis ≥ grade 2, at dose levels -1 and/or 1. 
In accordance with the conditions of supply agreement with MSD, ample notification will be provided to the sponsor 
and sites should alterations to the drug supply change. This is to allow time for appropriate adjustments to be made 
in regards to the patient’s treatment. 
 
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 
SELECTION OF PATIENTS 
4.1 
Screening and Enrolment 
The Investigator at site 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 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 34 of 
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protocol defined timelines. Written informed consent must be obtained prior to the patient undergoing any study 
specific procedures. 
 
4.2 
Registration 
When the patient signs the consent form they will be allocated that patient a trial ID that will be used to identify the 
patient for all future assessments.  Once all the screening assessments have been completed and the data entered on 
the CRFs the patient will be assessed for eligibility. If eligible the patient will begin on the trial. If the patient is not 
eligible then the local investigator will make alternative arrangements for the treatment of the patient. 
 
The trial ID will be a unique number that once assigned will become the permanent study identifier for that patient. 
In the event a patient is registered 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 eligibility has been confirmed.  To ensure patient 
confidentiality patients will only be identified on CRFs, other trial specific forms and all communication to RM-CTU 
using their assigned trial ID. It is the PI’s responsibility to maintain a confidential record of the identity i.e. full name 
and hospital number for the patients enrolled in this study along with their date of birth and assigned trial ID. At the 
end of the study this record should be archived along with the Site File. 
 
4.3 
Patient Replacement Strategy 
Additional patients may be enrolled in a given cohort to ensure that the required number of evaluable patients in 
each cohort is achieved. This includes patients that discontinue the trial for progressive disease within the DLT 
reporting period. A patient who discontinues the trial for a drug-related AE will not be replaced and will be counted in 
the evaluable population of patients for the respective cohort. However, patients found to have active pneumonitis 
on the day of their loading dose or day 1 of RT will be removed from the trial and can be replaced in that dose level 
cohort. Also patients who do not reach follow-up at cycle 3 for reasons other than progression or toxicity can be 
replaced by new patients in that cohort to ensure there is a minimum or 3 (or 6 if required) patients in each cohort. 
 
4.4 
Entry Criteria 
The following eligibility criteria were designed to select patients for whom the protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding 
whether this protocol is suitable for a particular patient. Eligibility criteria may not be waived by the investigator.  

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 35 of 
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4.4.1 
Inclusion Criteria 
In order to be eligible for participation in this trial, the patient must: 
1. Be willing and able to provide written informed consent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1. 
4. Histologically verified NSCLC including squamous cell carcinoma, adenocarcinoma, adenosquamous or large 
cell anaplastic carcinoma. 
5. Primary tumour in the thorax, where palliative RT is considered appropriate. Patients are permitted to have 
extra-thoracic disease that will not be encompassed in the RT field. This disease will be assessed for abscopal 
response 
6. Ability to tolerate a course of palliative RT to the lung. 
7. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumour 
lesion. 
8. Have a performance status of 0-1 on the ECOG Performance Scale. 
9. Demonstrate adequate organ function as defined in Table 2, all screening labs should be performed within 10 
days of confirmation of eligibility.   
 
System 
Laboratory Value 
Haematological 
• 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
• 
Platelets 
≥100,000 / mcL 
• 
Haemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
• 
Serum creatinineOR 
• 
Measured or calculatedacreatinine 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 patient 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 patients with total bilirubin levels > 1.5 ULN 
• 
AST (SGOT) and ALT (SGPT) 
 
≤ 3 X ULN  OR 
≤ 5 X ULN for patients with liver metastases 
Coagulation 
Prothrombin Time (PT) 
 
≤1.5 
X 
ULN 
unless 
patient 
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 patient is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
Table 2: Adequate Organ Function Laboratory Values 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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10. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours 
prior to confirmation of study eligibility.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.   
11. 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 6 months after the last dose 
of study medication.  Patients of childbearing potential are those who have not been surgically sterilised or 
have not been free from menses for > 1 year.  
12. Male patients should agree to use an adequate method of contraception starting with the first dose of study 
therapy through 6 months after the last dose of study therapy. 
13. Patient’s lung function tests at baseline should have an FEV1 > 0.8L or > 30%.  
 
4.4.2 
Exclusion Criteria 
The patient must be excluded from participating in the trial if the patient: 
1. 
Is currently participating in or has participated in a study of an investigational agent or using an 
investigational device within 4 weeks of the first dose of treatment. 
2. 
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. 
 
3. 
Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.  
4. 
Previous RT to the lung 
5. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or to baseline) from AEs due to a previously 
administered agent. 
- 
Note:  Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the 
study. 
- 
Note:  If patient received major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy.   
6. 
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.   
7. 
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  Patients with 
previously treated brain metastases may participate provided they are stable (without evidence of 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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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.   
8. 
Has an active automimmune 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.  Patients with vitiligo or resolved childhood asthma/atopy would be an exception 
to this rule.  Patients that require the use of bronchodilators or local steroid injections are not excluded from 
this study.  Patients with hypothyroidism stable on hormone replacement or Sjörgen’s syndrome will not be 
excluded from the study. 
9. 
Patients with evidence of interstitial lung disease, or history of pneumonitis (including non-infectious 
pneumonitis) that required steroids, or current pneumonitis (including non-infectious pneumonitis). 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in 
the best interest of the patient to participate, in the opinion of the treating investigator.   
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
12. 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 6 months after the last dose of trial treatment. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways). 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
16. 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 this treatment patients will be assessed 14 days (week 0) before RT, day 1 (week 2), day 8 (week 3), day 15 
(week 4) and day 22 (week 5) (high dose arm only) of RT and then every 3 weeks at the administration of their next 
dose of pembrolizumab until they have disease progression, unacceptable toxicities, discontinuation for other 
reasons or withdrawal from the study. Patients will also be required to attend a safety visit 30 days after their last 
dose of pembrolizumab.  

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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If the patient has not progressed at the last dose of pembrolizumab they will be reviewed every 9 weeks until the 
start of new anti-cancer therapy, disease progression, death, withdrawal or end of the study. 
 
Patients that have progressed or begin a new anti-cancer treatment will enter into the survival follow-up phase and 
will be reviewed every 12 weeks to assess for disease status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
 
The schedule of study assessment (Table 3) summarises the trial procedures to be performed at each visit.  Individual 
trial procedures are described in detail below.   
 
Furthermore, additional evaluations/testing may be clinically indicated for reasons related to patient 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. 
 
 
 
 
 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                       
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 39 of 100                                                                
 
 
1. 
Patients that do not have archival tissue must sign the study consent prior to undergoing a newly obtained biopsy 
2. 
Dose escalation and expansion cohort will not be enriched for PD-L1 strong patients. PD-L1 testing will be batched and performed once all patients are on study 
3. 
Pneumonitis should be assessed by a combination of clinical assessment and CXR or CT results. CXR shoul be used at screening, week2, cycle 1 and cycle 3. CT results should be used at cycle 2 
4. 
Only applicable if SFU is before cycle 4 of the maintenance period 
5. 
MRI/CT Imaging should occur at screening, cycle 2 and every 3 cycles (every 9 weeks) for the first 6 months then every 12 weeks after 6 months (regardless of treatment delays) Images can be up to 7 days before visit to ensure results at 
the visit. The same imaging technique should be used throught the trial 
6. 
Only applicable if the patient comes off for other reason than disease progression and no measurement had been taken within the last 4 weeks 
7. 
Pulmonary function tests at screening, cycle 1 and then every other cycle 
8. 
This visit is only applicable if the patient comes off the study between treatment cycles 
9. 
Or before the initiation of a new anti-cancer therapy 
10. 
Maintenance Pembrolizumab will continue until disease progression, withdrawal of consent or unacceptable toxicity. Patients obtaining CR or completing 35 cycles of treatment may discontinue treatment, with the option of restarting 
on progression 
Table 3.1: Study Schedule of Assessment (Low Dose Radiotherapy Arm) 
Safety 
Follow-up
(SFU)
Post 
Safety 
Follow-up
Survival 
Follow-up
C2
C3
C4
C5
C6
C7
C8
Wk
Wk
Wk
Wk
Wk
Wk
Wk Wk
Wk
Wk Wk Wk Wk Wk
0
2
3
4
5
6
7
8
11
14
17
20
23
26
Visit Window (Days):
-28 to -1
- 14 RT
D1 RT
D8
D15
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed Consent 1
X
Inclusion/Exclusion Criteria
X
Demographics, Medical & Treatment History
X
New Anti-Cancer Therapy Review
X
Survival Status
X
Adverse Events Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radiation Toxicity Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
X4
MRC Dyspnoea Score
X
X
X
X
X
X
Pneumonitis Assessment
X3
X3
X3
X3
X3
X4
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Tests
X
X
X
X
X7
Haematology and Biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FT3, FT4 and TSH
X
X
X
X
X
X
X
X
X
X
X
X
PT and aPTT
X
Urinalysis
X
Pregnancy Test - Urine/Serum
X
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
X
X10
Radiotherapy 
X
Tumour Imaging  - MRI/CT
CT/CXR
CXR
CXR
CT CXR
CT
CT5
CT6
Archival/New Tumour Biopsies
X
PD-1 Assessment2
X
Research Blood Collection
X
X
X
X
OPTIONAL Research Biopsies (Part B only)
X
X
Every 9 
wks from 
SFU
Every 12 wks 
from SFU
Administrative Procedures
Clinical Procedures / Assessments
Treatment Cycle/Week Title:
Screening
C1
Discontinuation
of IMP
30 days after 
last dose 9
LOW DOSE RADIOTHERAPY ARM
Trial Period:
Screening 
Phase
Pembrolizumab 
administration 2 weekly 
during Radiotherapy
Pembrolizumab administration 
3 weekly during Maintenance
(Can be repeated beyond 8 cycles)
End of 
Treatment
(If applicable) 8
Post-Treatment

 
 
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1. 
Patients that do not have archival tissue must sign the study consent prior to undergoing a newly obtained biopsy 
2. 
Dose escalation and expansion cohort will not be enriched for PD-L1 strong patients. PD-L1 testing will be batched and performed once all patients are on study 
3. 
Pneumonitis should be assessed by a combination of clinical assessment and CXR or CT results. CXR shoul be used at screening, week2, cycle 1 and cycle 3. CT results should be used at cycle 2 
4. 
Only applicable if SFU is before cycle 4 of the maintenance period 
5. 
MRI/CT Imaging should occur at screening, cycle 2 and every 3 cycles (every 9 weeks) for the first 6 months then every 12 weeks after 6 months (regardless of treatment delays) Images can be up to 7 days before visit to ensure results at 
the visit. The same imaging technique should be used throught the trial 
6. 
Only applicable if the patient comes off for other reason than disease progression and no measurement had been taken within the last 4 weeks 
7. 
Pulmonary function tests at screening, cycle 1 and then every other cycle 
8. 
This visit is only applicable if the patient comes off the study between treatment cycles 
9. 
Or before the initiation of a new anti-cancer therapy 
10. 
Maintenance Pembrolizumab will continue until disease progression, withdrawal of consent or unacceptable toxicity. Patients obtaining CR or completing 35 cycles of treatment may discontinue treatment, with the option of restarting 
on progression 
Table 3.2: Study Schedule of Assessment (High Dose Radiotherapy Arm) 
Safety 
Follow-up
(SFU)
Post 
Safety 
Follow-up 
Survival 
Follow-up
C2
C3
C4
C5
C6
C7
C8
Wk
Wk
Wk
Wk
Wk
Wk
Wk Wk Wk
Wk Wk Wk Wk Wk
0
2
3
4
5
6
7
9
12
15
18
21
24
27
Visit Window (Days):
-28 to -1
-14 RT
D1 RT
D8
D15
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed Consent 1
X
Inclusion/Exclusion Criteria
X
Demographics, Medical & Treatment History
X
New Anti-Cancer Therapy Review
X
Survival Status
X
Adverse Events Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radiation Toxicity Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
X4
MRC Dyspnoea Score
X
X
X
X
X
X
Pneumonitis Assessment 
X3
X3
X3
X3
X3
X4
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Tests
X
X
X
X
X7
Haematology and Biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FT3, FT4 and TSH
X
X
X
X
X
X
X
X
X
X
X
X
PT and aPTT
X
Urinalysis
X
Pregnancy Test - Urine/Serum
X
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
X
X
X10
Radiotherapy
X
X
X
Tumour Imaging - MRI/CT
CT/CXR
CXR
CXR
CT CXR
CT
CT5
CT6
Archival/New Tumour Biopsies
X
PD-1 Assessment2
X
Research Blood Collection
X
X
X
X
OPTIONAL Research Biopsies (Part B only)
X
X
Pembrolizumab administration 
3 weekly during Maintenance
(Can be repeated beyond 8 cycles)
Pembrolizumab administration 2 
weekly during Radiotherapy
C1
Administrative Procedures
Clinical Procedures / Assessments
Treatment Cycle/Week Title:
Screening
Every 12 wks 
from SFU
Discontinuation 
of IMP
30 days after 
last dose 9
Every 9 
wks from 
SFU
HIGH DOSE RADIOTHERAPY ARM
Trial Period:
Screening 
Phase
Post-Treatment
End of 
Treatment 
(If applicable) 8

 
 
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5.2 
Administrative Procedures/Assessments 
5.2.1 Informed Consent 
It is the responsibility of the Investigator / designee to give each patient, prior to inclusion in the trial, full and 
adequate verbal and written information regarding the objective and procedures of the trial and the possible risks 
involved. Sufficient time should be allowed for the patient to decide on trial entry. Patients must be informed about 
their right to withdraw from the trial at any time. Written patient information must be given to each patient before 
enrolment. The written patient information is an approved patient information sheet (PIS) according to national 
guidelines.  
 
The Investigator must obtain documented written informed consent from each potential patient prior to participating 
in a clinical trial. Consent must be documented by the patient dated signature on a consent form along with the 
dated signature of the person conducting the consent discussion. If the patient is illiterate, an impartial witness 
should be present during the entire informed consent reading and discussion. Afterwards, the patient should sign and 
date the informed consent, if capable. The impartial witness should also sign and date the informed consent along 
with the individual who read and discussed the informed consent. 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 patients and sign the consent form.  All signatures must be obtained before the 
occurrence of any medical intervention required by the protocol.   
 
A copy of the signed and dated consent form should be given to the patient before participation in the trial. The 
original consent form should be stored in the site file with a copy also being placed in the patient’s medical notes.  
Results from tests conducted as part of patients’ standard care may be used as part of screening to determine 
eligibility as long as the tests were conducted within the acceptable time window.  
 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the patient must receive the REC approval/favourable opinion in advance of use.  The patient 
should be informed in a timely manner if new information becomes available that may be relevant to the patient’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 patient’s dated 
signature. The informed consent will adhere to REC requirements, applicable laws and regulations. 
 

 
 
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Patients who achieve a CR or complete 35 cycles of maintenance pembrolizumab may discontinue treatment. They 
may restart maintenance pembrolizumab on disease progression. Provided their consent is on the current version of 
the PIS, patients are not required to re-consent to the trial on reinitiating maintenance pembrolizumab.  
 
5.2.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the 
patient qualifies for the trial.  
 
5.2.3 Demographic Data, Medical History and Treatment History 
Demographic data collected will include date of birth and race/ethnicity. A medical history will be obtained by the 
investigator /designee.  Medical history will include all active conditions, and any condition diagnosed within the prior 
10 years that are considered to be clinically significant by the Investigator.  In addition any abnormal and clinically 
significant results seen during the screening period should be recorded in the medical history form. Details regarding 
the disease for which the patient 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 patient’s current 
disease status and treatment history including:  
• 
Prior and current details regarding disease status  
• 
Review all prior cancer treatments including systemic treatments, radiation and surgeries  
 
5.2.4 Anti-Cancer Therapy Review 
Patients that discontinue from pembrolizumab for any other reason than progression will have a follow-up visit every 
9 weeks in which the investigator should review all new anti-cancer therapy initiated after the last dose of trial 
treatment.  If a patient initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 
days safety follow-up visit must occur before the first dose of the new therapy.  Once new anti-cancer therapy has 
been initiated the patient will move into survival follow-up. 
 
5.2.5 Survival Status 
The investigator or qualified designee will assess the patient for survival status at specified visits as defined in the 
schedule of study assessment (Table 3). The assessment will include the patient status and if applicable details of 
patient death or details if patient has been lost to follow up. 
 

 
 
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5.2.6 
Prior and Concomitant Medications Review 
5.2.6.1 Prior Medications 
The investigator / designee will review prior medication use, including any protocol-specified washout requirement, 
and record prior medication taken by the patient within 28 days before starting the trial.  Treatment for the disease 
for which the patient has enrolled in this study will be recorded separately and not listed as a prior medication.  
 
5.2.6.2 Concomitant Medications 
In addition the investigator / designee will record all medication, if any, taken by the patient during the trial.  All 
medications related to reportable SAEs and overdose and liver toxicity ECIs should be recorded as defined in Section 
7. 
 
5.3 
Clinical Procedures/Assessments 
5.3.1 
PD-1 Assessment 
To participate in the trial patients must have archived tissue of a tumour lesion not previously irradiated (tumours 
progressing in a prior site of radiation are allowed) for PD-L1 characterisation. Neither the dose escalation nor the 
dose expansion cohorts will be enriched for PD-L1 strong patients. This specimen will be batched and analysed 
retrospectively at a central laboratory for expression status of PD-L1 by immunohistochemistry (IHC). If no tissue is 
available then following informed consent they should undergo a biopsy of a tumour lesion for biomarker analysis.  
 
 
5.3.2 
Adverse Event (AE) Monitoring 
The investigator / designee will assess each patient for potential new or worsening AEs as specified in the schedule of 
study assessment (Table 3) and more frequently if clinically indicated.  AEs will be graded and recorded from first 
dose of pembrolizumab until the patients 30 days safety follow-up visit according to NCI CTCAE Version 4.0 (see 
Appendix 2).  Toxicities will be characterised in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
 
All AEs of unknown aetiology associated with pembrolizumab exposure should be evaluated to determine if it is 
possibly an event of clinical interest (ECI) or a potentially immunologic aetiology (irAE).  See Section 7 and Appendix 5 
regarding the identification, evaluation and management of AEs of a potential immunological aetiology.  Please refer 
to section 7 for detailed information regarding the assessment and recording of AEs.   
 

 
 
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5.3.3 
Radiation Toxicity Assessment 
RT toxicity will be documented using the LENT SOMA radiation toxicity grading system (Appendix 3). Assessments will 
take place weekly for 6 weeks beginning at week 2 and ending at week 7. Additional assessments of RT toxicity will be 
documented at each cycle of the maintenance phase. 
 
5.3.4 
Full Physical Exam 
The investigator / designee will perform a complete physical exam at screening period and the time points defined in 
the study schedule of assessment (Table 3).  Clinically significant abnormal findings should be recorded as AEs during 
the trial.   
 
5.3.5 
Directed Physical Exam 
For cycles that do not require a full physical exam as described in the schedule of assessment (Table 3), the 
investigator / designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.   
 
5.3.6 
Vital Signs 
The investigator /designee will take vital signs at screening, prior to the administration of each dose of trial treatment 
and at treatment discontinuation as specified in the schedule of study assessment (Table 3).  Vital signs should 
include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only. 
 
5.3.7 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator / designee will assess ECOG status (Table 4)at screening, prior to the administration of each dose of 
trial treatment and discontinuation of trial treatment as specified in the study schedule of assessment (table 3).   
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. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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* 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 ClinOncol 5:649-655, 1982.The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
Table 4: ECOG Performance Status 
5.3.8 Pulmonary Function Tests 
Spirometry assessments will be performed at screening and cycle 1, 3, 5 and 7 only of the maintenance period.  
 
5.3.9 MRC Dyspnea Scale 
The investigator or qualified designee will assess the patient’s dyspnoea using the MRC Dyspnoea Score (Appendix 6) 
at screening period and the time points defined in the study schedule of assessments (Table 3).   
 
5.3.10 Pregnancy Tests 
Female patients of childbearing potential should have a negative urine or serum pregnancy during screening and 
within 72 hours prior to confirmation of study eligibility.  If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.  Patients will be required to undergo an additional pregnancy test 
before commencing cycle 1 of the maintenance phase. 
 
5.3.11 Haematology, Clinical Biochemistry and Urinalysis (including FT3, FT4, TSH, PT, aPTT and β-hCG†) 
All Laboratory tests will be performed at screening and then certain assessments at every visit as defined in the 
schedule of study assessment (Table 3). Sample will be analysed by the local study site laboratory using standard 
methods for routine tests. The following variables (Table 5) will be measured: 
Haematology 
Chemistry 
Urinalysis 
Other 
Haematocrit 
Albumin 
Blood 
PT  
Haemoglobin 
Alkaline phosphatase 
Glucose 
aPTT 
Platelet count 
Alanine 
aminotransferase (ALT) 
Protein 
Free triiodothyronine (FT3) 
WBC (total and differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
Free thyroxine (FT4) 
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 † 
 
Absolute Lymphocyte Count  
Calcium Corrected 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphate 
 
 
 
Potassium   
 
 
 
Sodium 
 
 
 
Magnesium 
 
 

 
 
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Total Bilirubin 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine  
 
 
 
Creatinine Clearance 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
Table 5: Required Laboratory Assessments 
Laboratory tests for screening can be performed within 10 days prior to confirmation of eligibility.  After this all pre-
dose laboratory procedures should be conducted no more than 72 hours prior to dosing.  Results must be reviewed 
by the investigator / designee and found to be acceptable prior to each dose of trial treatment.  
 
5.3.12 Pneumonitis Assessment 
A screening pneumonitis score should be documented on the basis of clinical symptoms and screening CXR and CT 
scan. If there is evidence of active pneumonitis at that visit, the patient will not be permitted to continue in the study. 
Patients will then be re-assessed at week 2 (day 1 of RT) and cycle 1, 2 and 3 of the maintenance period. 
 
5.3.13 Tumour Imaging and Assessment of Disease 
5.3.13.1 Baseline tumour imaging 
Imaging should be undertaken to confirm that the patient has a primary tumour in the thorax, where palliative RT is 
considered appropriate and the lesion is measurable using RECIST v1.1. The scan will also be assessed for an extra-
thoracic disease; if present these lesions will be used to assess for abscopal response 
 
5.3.13.2 Timing and Assessment of Disease 
Tumour imaging may be performed by CT or magnetic resonance imaging (MRI), but the same imaging technique 
should be used in a patient throughout the trial. The initial tumour imaging will be performed no more than 28 days 
prior to confirmation of eligibility. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within the correct time window.  
 
On-study imaging will be performed at screening then at cycle 2 to assess RT response. After cycle 2 imaging will be 
performed every 3 cycles (every 9 weeks) for the first 6 months (± 7 days) then every 12 weeks after 6 months, and 
should follow calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle 
frequencies.   
 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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Local investigator assessment will be used to determine eligibility and for patient management. Tumour imaging and 
assessment per local standard of care should be performed for patient management, and may include additional 
imaging (e.g. bone scan for lung cancer patients).  
 
Imaging should continue to be performed until documented disease progression, the start of new anti-cancer 
treatment, withdrawal of consent, death, or the end of the study, whichever occurs first.  
 
5.3.13.3 Confirmation of Disease Response  
Per RECIST v1.1 (Appendix 4), response should be confirmed by a repeat radiographic assessment no less than 4 
weeks from the date the response was first documented. The scan for confirmation of response may be performed at 
the earliest 4 weeks after the first indication of response, or at the next scheduled scan, whichever is clinically 
indicated. 
 
5.3.13.4 Confirmation of Disease Progression 
Disease progression should be confirmed at least 4 weeks after the first scan indicating progressive disease in 
clinically stable patients. Patients who have unconfirmed disease progression may continue on treatment until 
progression is confirmed. 
Clinically stable is defined by one or more of the following criteria: 
• 
Absence of signs and symptoms indicating disease progression 
• 
No decline in ECOG performance status 
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumour at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention 
 
 
5.3.14 Tumour Tissue Collection and Correlative Studies Blood Sampling 
5.3.14.1 Archival Tumour tissue samples 
For patients where a screening biopsy is not feasible, archival tumour material must be provided. If archived biopsy 
(block or slides) are sent it must contain tumour tissue. If no block is available, 10 or more freshly prepared 
(generated within the last 6 months) unstained 5 micron sections should be provided. Archival tumour blocks will be 
returned to source at the end of the study or, upon request, earlier if required for the patient’s clinical management. 
Cut sections will be retained by the study team. These are archived samples and as such participating patients will not 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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need to attend extra visits or undergo extra procedures. All collected archival samples will be classed as pre-
treatment samples and used as such in the immunological evaluation as described below. 
 
5.3.15 Tumour Biopsies and Research Blood Samples 
For patients without archived samples tumour biopsies will be obtained during the screening period and if the patient 
consents optional research blood samples will be obtained at week 0, week 4, cycle 2 and end of study visit (Disease 
Progression). 
Tumour and blood samples from this study may undergo proteomic, genomic and transcriptional analyses. Additional 
research may evaluate factors important for predicting responsiveness or resistance to pembrolizumab therapy and 
RT. Assays may include, but are not limited to: 
• 
Characterisation of TILs and tumour antigens 
Immunohistochemistry (IHC) will be used to assess the number and composition of immune infiltrates in 
order to define the immune cell subsets present within formalin-fixed, paraffin embedded (FFPE) tumour 
tissue before and after exposure to therapy. These IHC analyses will include, but not necessarily be limited to, 
the following markers: CD4, CD8, FOXp3, PD-1, PDL1, and PD-L2. 
• 
ctDNA 
Research blood samples will be analysed for ctDNA. 
 
5.3.16 Optional Fresh Tumour Biopsies and Processing/Storage 
The collection of fresh tumour tissue is entirely OPTIONAL and will only be considered in consenting patients during 
the dose expansion phase ONLY. At least 6 paired biopsies will be collected, with a minimum of 2 patients with 
squamous cell histology and 2 patients with non-squamous histology. 
All potentially biopsiable patients will have their most recent computerised tomography (CT) (preferably within the 
last 4 weeks) discussed with a Consultant Radiologist (tumour stream radiologist or interventional radiologist) will 
decide if 2 paired core biopsies can be safely performed in potential patients. If 2 paired core biopsies can safely be 
considered, the site to be biopsied (e.g. hepatic biopsy, lung biopsy, or percutaneous biopsy of subcutaneous lesion) 
and the modality of imaging to be used (e.g. CT guidance, ultrasound scan (USS) guidance) will be advised on. These 
will only be performed if they are felt safe in the opinion of the Consultant Radiologist. All CT guided liver and lung 
biopsies, will be performed by the Interventional Radiologist at the Chelsea site. Ultrasound guided liver and 
percutaneous biopsies can be performed at either site by a Consultant Radiologist.   
 

 
 
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If a bronchoscopy guided biopsy is required, this will need to be discussed further with the Honorary Respiratory 
Consultant at the Sutton site. If the Honorary Respiratory Consultant feels that paired biopsies can be performed 
safely, then this will need to be organised through the Sutton site.  
 
Consenting patients will have biopsies considered at 2 time points: 
A. Baseline  
B. At 8 – 9 weeks (around cycle 2 ± 3 days) 
 
The biopsy will be performed under sterile conditions with a trucut biopsy device (under radiological guidance, if 
indicated) using standard biopsy procedures. The specimen will be immediately transferred to the recommended 
storage solution and processed to either fresh frozen sample or paraffin wax. All FFPE tissue will be stored at room 
temperature and all frozen tumour samples will be stored at -80oC.  
All standard operating procedures for organising ultrasound guided biopsies, CT guided biopsies and bronchoscopy 
guided biopsies at the Royal Marsden NHS Foundation Trust must be adhered to. This includes performing a full 
blood count, biochemistry and coagulation studies within the specified trust guidelines. Further, the lead medical 
team should ensure the patients are given appropriate advice about anti-platelets drugs (e.g. aspirin and clopidogrel), 
oral anticoagulants (e.g. warfarin, dabigatran, rivaroxaban and apixaban) and low molecular weight heparins (e.g. 
enoxaparin, dalteparin, and tinzaparin). Where possible, the biopsy should be performed before 1 pm to allow for 
routine post-procedure observations during working hours.   In addition to having signed the consent for this clinical 
trial protocol, all patients undergoing a biopsy must sign the appropriate Royal Marsden NHS Foundation Trust 
imaging-guided biopsy consent form. This consent must be taken by the doctor performing the biopsy. A new consent 
must be done for each paired biopsy performed.  
Risks associated with research biopsies:  
A. Hepatic biopsies have a mortality rate of 0.13-0.33% and a complication rate of 5.9% (including all major and 
minor events - the majority of these comprising of post-procedure pain or non-significant haematomas (Gut 
1999;45:IV1-IV11 doi:10.1136/gut.45.2008.iv1).  
B. Percutaneous Lung Biopsies have a mortality rate 0.15% and complications that can include pneumothorax 
(0-61%), pulmonary haemorrhage (5-16.9%) and haemothorax (1.5%) (Thorax 2001;56:i1-i21 
doi:10.1136/thx.56.suppl_1.i1)  
C. Bronchoscopic biopsies have a mortality rate of 0.04% and a major complication rate of 1.2 per 10 000 
procedures based on a series of 40 000 UK patients. Major complications can include respiratory depression, 
pneumonia or pneumothorax (Thorax 2001;56:i1-i21 doi:10.1136/thx.56.suppl_1.i1).  

 
 
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5.3.17 Chain of Custody of Biological Samples 
In all cases, patients 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 patients 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.  
5.4 
Total Blood Volume 
The total volume of blood that will be drawn from each trial patient for the assessments described in the sections 
above is shown in Table 6. Up to 60 mL of optional blood will be collected for translational research. Examples of 
tubes used to collect these samples include, but not limited to:  
• 
3 mL Tempus™ Blood RNA Tubes 
• 
4.5 mL Lithium Heparin Coated Tubes 
• 
5 mL or 9 mL K3 EDTA Coated Tubes 
 
Sample volume (mL) 
No. of samples 
Total volume (mL) 
Routine Haematology 
61 
14 
84 
Routine Clinical chemistry 
81 
14 
112 
Total: 196 
Research Blood Samples – OPTIONAL  
Up to 60 
4 
Up to 240 
Study Total: 436 
Table 6: Volume of blood to be drawn from each trial patient for the duration of the trial; calculations based on 11 
administrations of pembrolizumab (Duration of RT and 8 cycles of the maintenance phase), a screening visit and 30 
days post end of treatment safety visit. 
Blood volumes for haematology and clinical chemistry may vary according to local practice 
 
6.0 
TREATMENTS 
Patients will be given pembrolizumab in addition to palliative RT. 

 
 
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6.1 
Standard Treatment 
6.1.1 
External Beam radiotherapy – Planning and Treatment 
Patients will be treated with external beam RT. Planning will be done by CT virtual simulation. Isodose intervention is 
required for the high dose group but not mandated for the low dose group. For the high dose group conformal 
planning with CT is permitted. The use of IV contrast is permitted if felt necessary. The gross target volume (GTV) will 
be defined as visible tumour on a planning CT scan (virtual simulation). 3D dose-volume information for the tumour 
and the normal tissues will be obtained for subsequent analysis. The normal structures to be outlined for post 
treatment analysis are lungs, heart and spinal cord. The CTV/PTV margin will be defined using standard Royal 
Marsden Hospital criteria. Dose will be prescribed at the midpoint or at 100% as per ICRU guidelines. Treatment 
verification with on-board imaging will be carried out as per departmental protocol. 
 
6.1.2 
Radiotherapy Dose 
Lesion(s) will be irradiated to either a dose of 20Gy in 5 fractions or 36Gy in 12 fractions. 
 
6.1.3 
Radiotherapy Assessments and Procedures 
6.1.3.1 Radiotherapy Toxicity Assessment 
A baseline pneumonitis score should be documented on the basis of clinical symptoms and screening CT scan. If there 
is evidence of active pneumonitis at that visit, the patient will not be permitted to continue in the study. 
RT toxicity will be documented at day 1, day 8 and 15 for low dose RT and day 1, 8, 15 and 22 for high dose RT. RT 
toxicity will be documented at cycle 1 (2 weeks from RT) ,2 (5 weeks from RT), 3 (8 weeks from RT) and maintenance. 
Specific toxicity with CTCAE v4.0 grading to be recorded for RT toxicity includes pneumonitis, lung fibrosis, 
oesophagitis, skin toxicity, myelitis and fatigue. All other AE are to be documented in addition.  
 
6.2 
Trial Treatment - Pembrolizumab 
6.2.1 
Investigational Product 
The Investigational Medicinal Product (IMP) for this study is Pembrolizumab. A potent and highly-selective humanised 
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. 
Pembrolizumab will be manufactured by MSD according to Good Manufacturing Practice and will be provided in the 
formulation as described in the table below. Additional information about the investigational product can be found in 
the Investigator’s Brochure (IB) . 
 

 
 
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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Table 7: Product Description 
6.2.2 
Product Preparation 
The pembrolizumab solution for infusion is a sterile, non-pyrogenic aqueous solution supplied in single-use Type I 
glass vial containing 100 mg/4 mL of pembrolizumab. The product is preservative-free solution which is essentially 
free of extraneous particulates. 
 
6.2.3 
Storage and Handling 
6.2.3.1 Storage  
The original solution for infusion should be stored at refrigerated conditions (2 – 8 °C). Vials should be stored in the 
original box to ensure the drug is protected from light. 
 
Prepared infusion solutions may be stored at room temperature for a cumulative time of up to 6 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 24 hours. If refrigerated, allow the vials and/or IV bags to 
come to room temperature prior to use.  
 
6.2.3.2  Handling 
Infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose 
Injection, USP (5% dextrose) and the final concentration of pembrolizumab in the infusion solutions should be 
between 1.0 mg/mL and 10.0 mg/mL. 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.  
 
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. 
 

 
 
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Sites should follow their SOPs for drug transport and delivery, with all possible effort to minimise agitation of the 
reconstituted drug product between the pharmacy and the clinic. 
 
Please 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 authorised person at the trial site. Trial medication may not be used for any 
purpose other than that stated in the protocol. 
 
6.2.4 Packaging and Labelling Information 
Pembrolizumab will be supplied by Merck, Sharp and Dohme (MSD) as solution 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.  
 
6.2.5 Returns and Reconciliation 
The investigator / designee is responsible for keeping accurate accountability records for pembrolizumab including 
the amount dispensed to and returned for each patient and the amount remaining on site at the conclusion of the 
trial.  
Upon completion or termination of the study, partially used trial medication will be destroyed at the site per 
institutional policy. It is the Investigator’s/designees responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 

 
 
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Upon completion or termination of the study, all unused trial medication will be returned to MSD or destroyed at the 
site per institutional policy. It is the Investigator’s/designees responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
 
6.2.6 Doses and treatment regimens 
All patients will receive pembrolizumab administered as per standard procedures following manufacturer’s 
instructions. Two dose levels of pembrolizumab will be studied to ensure tolerability of combining therapy with RT 
with the option after the first dose level to de-escalate. The treatment regimen to be used at each dosing level is 
outlined in Table 8 below. 
Drug 
Dose Level 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumab 
-1 
50mg 
Q2W 
IV infusion 
During RT phase 
Pembrolizumab 
1 
100mg 
Q2W 
IV infusion 
During RT phase 
Pembrolizumab 
2 
200mg 
Q2W 
IV infusion 
During RT phase 
Pembrolizumab maintenance 
200mg 
Q3W 
IV infusion 
Maintenance phase 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 6.2.9.2. 
Table 8: Pembrolizumab treatment regimens for each dosing level. 
Trial treatment should begin within 3 days of confirmation of eligibility or as close as possible to the date on which 
treatment is allocated/assigned. 
 
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. 
 
6.2.7 
Timing of Dose Administration 
Trial treatment should be administered on an outpatient basis on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the Study Flow Chart (Section 3.3) and on the schedule 
of study assessment (Table 3). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 
of each cycle due to administrative reasons. Trial treatment will be administered on day 1 of RT for low dose arm and 
day 1 and day 15 of the high dose arm. Both arms receive a preloading dose 2 weeks before RT. After RT patients will 
continue onto the maintenance phase. This will begin at week 5 for low dose patients and week 6 for high dose 
patients. Trial treatment during the maintenance phase of the trial is administered on a 3 weekly cycle. Maintenance 

 
 
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Pembrolizumab will continue until disease progression, withdrawal of consent, or unacceptable toxicity. Patients 
obtaining CR or having completed 35 cycles of Pembrolizumab have the option of discontinuing treatment, with a 
view to restarting treatment on disease progression. Retreatment should be discussed with the Chief Investigator and 
the study sponsor. Study related assessment and procedures should be as for the Pembrolizumab Maintenance 
phase, during the non-DLT period (see Table 3). Patients do not need to re-sign the consent form for restarting 
treatment, provided their consent is on the most up-to-date version of the Patient Information Sheet Consent Form. 
 
All trial treatments will be administered on an outpatient basis. Pembrolizumab will be administered as a 30 minute 
IV infusion (treatment cycle intervals or infusion length may be increased due to toxicity as described in Section 
6.2.9.2).  Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given 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 6.4.1.4. 
 
The pharmacy manual contains specific instructions for pembrolizumab, reconstitution, preparation of the infusion 
fluid, and administration. 
 
6.2.8 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and patient will know the treatment administered. 
 
6.2.9 
Dose Selection/Modification 
6.2.9.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 1.3 – Background and Rationale.   
6.2.9.2 Dose Modification 
Pembrolizumab will be withheld for drug-related Grade 4 haematological toxicities and non-haematological toxicity ≥ 
Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as per table below. 
Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhoea/Colitis 
2-3 
 
Toxicity resolves to 
Grade 0-1/baseline. 
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 
Increased 
Bilirubin 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 

 
 
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Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
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 patients 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.  
If recurrent grade 2 
pneumonitis occurs 
pembrolizumab should 
be permanently 
discontinued. 
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 
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. 
3-4 
Permanently discontinue 
Permanently discontinue 
Hepatitis  
1 
Continue treatment 
 
2 
Withhold treatment 
Treat with steroids (prednisone 1 – 2 mg/kg or 
equivalent). Restart treatment when all liver function 
tests are down to grade 1 and steroid dose is down to 10 
mg or less of prednisone or equivalent. Based on severity 
and symptoms you may wish to discontinue treatment.  
3 - 4 
Permanently discontinue 
Permanently discontinue 
Encephalitis 
3 - 4 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
1 - 2 
Withhold treatment 
Treat with steroids (prednisone 1 – 2 mg/kg or 
equivalent). Restart treatment when symptoms are down 
to grade 1 and steroid dose is down to 10 mg or less of 
prednisone or equivalent. 
3-4 
Permanently discontinue 
Permanently discontinue 
Skin reactions 
1 – 2  
Continue treatment  
Manage with topical corticosteroids and oral anti-puritics 
3 
Withhold treatment 
Treat with steroids (prednisone 1 – 2 mg/kg or 
equivalent). Restart treatment when rash is down to 
grade 1 and steroid dose is down to 10 mg or less of 
prednisone or equivalent. 
4 
Permanently discontinue 
Permanently discontinue 
Confirmed 
Stevens-Johnson 
Syndrome or 
- 
Permanently discontinue 
Permanently discontinue 

 
 
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Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Toxic-epidermal 
Necrolysis 
Guillain-Barré 
syndrome 
3 - 4 
Permanently discontinue 
Permanently discontinue 
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 patients 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 patients should be discontinued. 
2 Patients 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 9: Dose modification guidelines for drug-related AEs 
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. Patients 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 AEs, see section 7.   
 
Patients 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. RT-related AEs will be managed as per 
institution clinical guidelines. 
 
Events of Clinical interest (ECI) can be potential immune related AEs and dose modifications for these toxicities 
should they occur can be found in appendix 5 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study 
therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the patient's study record. 
 
6.3 
Concomitant medications 
Concomitant medications will be recorded at screening and at every visit during the treatment phase of the study in 
the case report form (CRF) in the concomitant therapy section. 

 
 
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6.3.1 
Prohibited Concomitant Medications 
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 the patient may be 
discontinue from trial therapy.  The investigator should discuss any questions regarding this with the Chief 
Investigator ([CI] or delegate).   
 
The final decision on any supportive therapy or vaccination rests with the investigator and/or the patient's primary 
physician.  However, the decision to continue the patient on trial therapy schedule requires the mutual agreement of 
the Investigator, CI/ delegate, and the patient.  
 
Patients are prohibited from receiving the following therapies during the Screening and Treatment Phase of this trial: 
• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Radiation therapy not specified in this protocol 
o Note:  subsequent RT whilst on maintenance treatment will not be permitted. Radiation therapy to a 
symptomatic solitary lesion or to the brain may be allowed after consultation with Sponsor providing 
it does not involve re-irradiation of any part of the lung  
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial.  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 aetiology.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the CI/delegate.  
Patients 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.  Patients 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. 
 

 
 
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6.3.2 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’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 
case report form (CRF) including all prescriptions, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, and date may 
also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after the last 
dose of trial treatment or initiation of other anti-cancer therapies should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should only be recorded for SAEs and overdose and 
liver toxicity ECIs as defined in Section 7. 
 
6.4 
Rescue Medications & Supportive Care 
6.4.1 
Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating investigator 
including but not limited to the items outlined below: 
 
6.4.1.1 Diarrhoea: 
Patients 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 patients, infectious etiologies should be ruled out, and if symptoms are persistent and/or severe, 
endoscopic evaluation should be considered. 
• 
In patients 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 patients 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 less, corticosteroid 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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taper should be started and continued over at least 1 month.  Guidelines for continuing treatment 
with pembrolizumab can be found in Appendix 5. 
All patients 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. 
 
6.4.1.2 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.  Patients should be 
strongly encouraged to maintain liberal oral fluid intake. 
 
6.4.1.3 Anti-infectives: 
Patients 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. 
 
6.4.1.4 Immune-related adverse events: 
Please see Section 6.5 below regarding diagnosis and management of adverse experiences of a potential 
immunologic aetiology.   
 
6.4.1.5 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. 
 
The table below shows treatment guidelines for patients who experience an infusion reaction associated with 
administration of pembrolizumab. 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
 
None 
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 patient 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 patient should be pre-
medicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Patient 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 patient is deemed medically 
stable in the opinion of the investigator. 
Hospitalisation may be indicated. 
Patient 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 10: Infusion Reaction Treatment Guidelines 

 
 
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6.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related 
Events of Clinical Interest (irECI) 
Immune-related Adverse events (IrAEs) may be defined as an adverse event of unknown aetiology, associated with 
drug exposure and is consistent with an immune phenomenon.  irAEs may be predicted based on the 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 labelling an adverse event as an irAE.  Patients 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 are detailed in the table below. 
 
irAE 
Withhold/Discontinue pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May 
withhold 
pembrolizumab. 
For 
recurrent 
grade 
2 
pneumonitis, 
Pembrolizumab should be discontinued 
permanently. 
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. 
Based on limited data from clinical studies in subjects 
whose immune-related adverse reactions could not 
be controlled with corticosteroid use, administration 
of other systemic immunosuppressants can be 
considered. 
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 utilise 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. Based on limited data from clinical studies in 
subjects whose immune-related adverse reactions 
could not be controlled with corticosteroid use, 
administration 
of 
other 
systemic 
immunosuppressants can be considered. 
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 11: General Approach to Handling irAEs 
Details for managing specific irAEs are summarised below: 
 
Immune-mediated pneumonitis 

 
 
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Monitor subjects for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with radiographic 
imaging and exclude other causes. Administer corticosteroids for Grade 2 or greater events (initial dose of 1-2 
mg/kg/day prednisone or equivalent followed by a taper), withhold pembrolizumab for moderate (Grade 2) 
pneumonitis, and permanently discontinue pembrolizumab for recurrent moderate (Grade 2), severe (Grade 3) or 
life-threatening (Grade 4) pneumonitis. 
 
Immune-mediated colitis 
Monitor subjects for signs and symptoms of colitis and exclude other causes. Administer corticosteroids for Grade 2 
(if persists for >3 days) or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), 
withhold pembrolizumab for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue 
pembrolizumab for life-threatening (Grade 4) colitis. 
 
Immune-mediated hepatitis 
Monitor subjects for changes in liver function (at the start of treatment, periodically during treatment and as 
indicated based on clinical evaluation) and symptoms of hepatitis and exclude other causes. Administer 
corticosteroids (initial dose of 0.5-1 mg/kg/day [for Grade 2 events] and 1-2 mg/kg/day [for Grade 3 or greater 
events] prednisone or equivalent followed by a taper),1-2 mg/kg/day prednisone or equivalent followed by a taper) 
and, based on severity of liver enzyme elevations, withhold or discontinue pembrolizumab. 
 
Immune-mediated nephritis 
Monitor subjects for changes in renal function and exclude other causes. Administer corticosteroids for Grade 2 or 
greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold pembrolizumab 
for moderate (Grade 2), and permanently discontinue pembrolizumab for severe (Grade 3) or life-threatening (Grade 
4) nephrits. 
 
Immune-mediated endocrinopathies 
Monitor subjects for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency) and exclude other causes. Administer corticosteroids to treat secondary adrenal insufficiency and other 
hormone replacement as clinically indicated, withhold pembrolizumab for moderate (Grade 2), withhold or 
discontinue pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) hypophysitis. 
 
Monitor subjects for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, 
and withhold pembrolizumab in cases of severe hyperglycemia until metabolic control is achieved. 
 

 
 
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Thyroid disorders have been reported in subjects receiving pembrolizumab and can occur at any time during 
treatment; therefore, monitor subjects 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. 
Hypothyroidism may be managed with replacement therapy without treatment interruption and without 
corticosteroids. Hyperthyroidism may be managed symptomatically. Withhold or discontinue Pembrolizumab for 
severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism. For subjects with severe (Grade 3) or life-threatening 
(Grade 4) endocrinopathy that improves to Grade 2 or lower and is controlled with hormone replacement, 
continuation of pembrolizumab may be considered. 
 
Other immune-mediated AEs 
The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% 
(unless otherwise indicated) of subjects treated with pembrolizumab: uveitis, myositis, Guillain-Barré syndrome, 
pancreatitis and severe skin reactions (1.1%). 
 
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 Table 13 in section 7.5. Patients 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 to the Sponsor who will in turn notify MSD. If the irECI is determined to be associated please refer to Appendix 
5 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 
patient.  Any additional questions of the collection or information on management of irECIs should be directed to the 
Sponsor. 
6.6 
Supportive Care Guidelines for Pneumonitis 
Patients 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 patient is determined to have study drug associated pneumonitis, the suggested treatment plan is detailed in 
Table 12. 
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 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
Conduct an in person evaluation approximately twice per week 

 
 
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Grade 1 or resolves within 12 
weeks 
Second episode of pneumonitis – 
discontinue pembrolizumab if upon 
re-challenge the patient develops a 
second episode of Grade 2 or 
higher pneumonitis. 
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 patient 
Bronchoscopy with biopsy and/or BAL is recommended. 
Immediately treat with intravenous steroids (methylprednisolone 125 
mg IV). When symptomsimprove to Grade 1 or less, a high dose oral 
steroid (prednisone 1 to 2 mg/kg once per day ordexamethasone 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 retapering 
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 12: 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 – permanently discontinue pembrolizumab if upon re-challenge patient 
develops pneumonitis  Grade 2 
 
6.7 
Diet/Activity/Other Considerations 
6.7.1 
Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such as diarrhoea, nausea 
or vomiting. 
6.7.2 
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 1 highly effective method of birth control that can be combined to a second method of 
contraception (not considered highly effective) or they are considered highly unlikely to conceive.  Highly unlikely to 
conceive is defined as 1) surgically sterilised, 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 

 
 
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of the study.  Thehighly effective birth control method can be combined to the adequate barrier methods of 
contraception. Patients should start using birth control from screening throughout the study period up to 6 months 
after the last dose of study therapy. Male patients 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 6 months 
after the last dose of study therapy. 
The following are considered as highly effective birth control methods: Combined oral/intravaginal/transdermal 
contraceptive agent associated with inhibition of ovulation (which contains estrogen and progestogen both), 
Progestogen only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, Copper 
intrauterine device (IUD), Intrauterine hormone-releasing system (IUS), Bilateral tubal occlusion, Vasectomised 
partner provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised 
partner has received medical assessment of the surgical success and Sexual abstinence, the reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject 
The following are considered adequate barrier methods of contraception and can be combined to a highly effective 
birth control method: diaphragm, condom (by the partner), sponge, or spermicide.   
 
Patients 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 patient will not reliably comply with the requirements for contraception, that patient 
should not be entered into the study. 
 
6.7.3 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the patient will immediately be 
removed from the study.  The site will contact the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
and to MSD without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or newborn).  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 without delay and within 24 hours to the sponsor. If a male 
patient impregnates his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the RM-CTU and followed as described above and in Section 7. 

 
 
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6.7.4 
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, patients who are breast-feeding are not 
eligible for enrolment. 
 
6.7.5 
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 7.6 for definitions and reporting procedures. 
6.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study 
6.8.1 
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, please see Section 5.3.13 
Note: For unconfirmed radiographic disease progression. 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 
• 
Completed 35 cycles of treatment with pembrolizumab 
 
Trial patients will not be enrolled more than once. The primary reason for discontinuation should be recorded on the 
CRF. 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 assessment (Table 3). After the end 
of treatment, patients will continue to be assessed for AE and SAE monitoring until completion of the safety follow up 
visit. 
Follow-up actions for patient discontinuing the trial are as follows: 
 
• 
All patients will be required to: 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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o Attend a safety follow-up 30 days after their last dose of pembrolizumab, 
 
• 
If a patient progresses or begins a new anti-cancer treatment they will be required to: 
o Undertake survival status assessments every 12 weeks until death, withdrawal of consent, lost to 
follow up or the end of the study. 
 
• 
If a patient discontinues for reasons other than progression during treatment and does not withdraw their 
consent to follow up they will be required to: 
o Attend follow-up assessments every 9 weeks until disease progression, initiation of a new anti-cancer 
treatment death, end of the study.  Information regarding post-study anti-cancer treatment will be 
collected if new treatment is initiated. 
 
6.9 
Withdrawal from the Study 
Patients have the right to discontinue study treatment any time for any reason, without prejudice to their medical 
care. 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 
Patients may withdraw consent at any time for any reason or havetrial treatment stopped 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 AEs that 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 35 cycles of treatment with pembrolizumab may discontinue treatment 
with the option of restarting treatment on disease progression. Retreatment should be discussed with the Chief 
Investigator and the study sponsor. Study related assessment and procedures should be as for the Pembrolizumab 
Maintenance phase, during the non-DLT period (see Table 3). Patients do not need to re-sign the consent form for 
restarting treatment, provided their consent is on the most up-to-date version of the Patient Information Sheet 

 
 
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Consent Form. After discontinuing treatment following assessment of CR, these patients should return to the site for 
a 30 days safety follow-up visit and then proceed to the follow-up period of the study. 
 
7.0 
PHARMACOVIGILANCE 
7.1 
Adverse events 
7.1.1 
Adverse Event Definition: 
An adverse event is defined as any untoward undesired or unplanned occurrence (including deterioration of a pre-
existing medical condition) in a patient administered a pharmaceutical product or undertaking a protocol-specified 
procedure. 
 
An AE can therefore be any unfavourable and unintended sign, symptom or disease and/or laboratory or 
physiological observation associated with the use of a medicinal product or protocol-specified procedure but does 
not necessarily have to have a causal relationship to this treatment or 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 pembrolizumab 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 AEs.  Examples of this may include, but are not limited to, onset of menses 
or menopause occurring at a physiologically appropriate time. 
AEs may also occur in screened patients during any pre-allocation baseline period as a result of a protocol-specified 
intervention, including washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
7.1.2 
Adverse Reaction Definition: 
An AE assessed by the Principal Investigator and / or Chief Investigator as reasonably likely to be related to the 
administration of a medicinal product or protocol-specified procedure. 
7.1.3 
Disease Progression 
Disease progression of the cancer under study is not considered an adverse event unless it results in hospitalisation. 
7.1.4 
New Cancers 
The development of a new cancer should be regarded as an SAE and reported accordingly.  
 

 
 
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7.1.5 
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.   
7.1.6 
Pregnancy and Lactation 
Pregnancy and lactation are not considered AEs, however these events should be reported to the RM-CTU following 
guidance in section 7.7 
7.2 
Assessing and Recording Adverse Events 
All AEs will be recorded from the first dose until the safety follow-up in the CRF. They will be followed up according to 
local practice until the event has stabilised or resolved, or the follow-up visit has taken place, whichever is the sooner. 
SAEs will also be recorded throughout the study. The reporting timeframe for AEs meeting any serious criteria is 
described in section 7.4.1. 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events resolve, 
stabilise or the patient completes the trial.  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 CRF.  
If an Investigator learns of any AE that he/she consider serious, 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 CRF 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 
For the pre-registration period AEs will not be collected in patients that have not undergone any protocol-specified 
procedure or intervention.  If the patient requires a blood draw, fresh tumour biopsy etc. for the study then the 
patient will be required to consent to the main study and AEs will be captured as described above. 

 
 
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7.3 
Evaluating Adverse Events 
AEs will be evaluated by an investigator who is a qualified medical physician. 
7.3.1 Determining AE Severity and Grade 
AE severity and grade will be evaluated according to the CTCAE v4.0 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 
 
7.3.2 
Determining AE Causality 
The Principal Investigator must endeavour to obtain sufficient information to assess the causality of the AE and must 
provide his/her opinion whether the event has any relationship to the administered study treatment / procedure. 
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). 

 
 
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• 
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. 
 
7.4 
Serious adverse events (SAEs) 
A ‘serious adverse event’ is defined in Article 2(o) of Directive 2001/20/EC as follows:  
 
Any untoward medical occurrence or effect that at any dose that: 
 
• 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; 
• Requires in-patient hospitalisation or prolongs existing in-patient hospitalisation2 
• Results in persistent or significant incapacity or disability; 
• Is a new cancer 
• Is a congenital anomaly or birth defect; 
• Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an 
overdose is considered a serious adverse event.  
• Is any other medically important event.3 
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). 
3 A medically important event 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 that may jeopardise the patient 
and require medical or surgical intervention to prevent one of the outcomes listed above. 
 
7.4.1 
Reporting SAEs 
All SAEs regardless of causality, pregnancy or overdose that occur from the first dose until the 30 days safety follow-
up or the initiation of a new anticancer therapy, whichever is earlier, must be reported on the SAE report form within 
24 hours to the sponsor of the investigator / designee becoming aware of the event.  
 
The SAE form should be sent to  
Email: Pear.Trial@rmh.nhs.uk 

 
 
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Fax: 020 8915 6762  
who will in turn notify MSD of the event. 
 
The SAE form must be completed, assessed for causality and expectedness against the Reference Safety Information.  
then signed and dated by the Principal Investigator or an appropriately qualified designated individual identified on 
the delegation log. The IB as last amended and approved by the national competent authority serves as the reference 
safety information for the assessment of the expectedness of any adverse reaction that might occur during the 
clinical trial. The report will then be reviewed by the Chief Investigator (or a nominated representative) to confirm 
relatedness and expectedness. The NCI CTCAE Version 4.0 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 on 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. The sponsor will in turn 
submit the updated report to MSD. 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 the IMP or protocol-
specified procedure 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 inform MSD. 
 
7.4.2 
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 
CRF.   
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 such as pharmacokinetic 
sampling according to the trial protocol, is also exempt from being reported as an SAE. 
3. Progressive disease and death due to disease are not considered SAE’s but should be reported in the CRFs 
7.4.3 
Determining SAE Causality and Expectedness 
Assessment of causality and expectedness for all SAEs will be made by the PI/designee and Chief Investigator or 
delegate against the Reference Safety Information. The IB as last amended and approved by the national competent 

 
 
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authority serves as the reference safety information for the assessment of the expectedness of any adverse reaction 
that might occur during the clinical trial. .  If updated versions of the IB are released during the course of the trial then 
assessment of expectedness will be made against the current regulatory approved version. 
 
7.5 
Events of Clinical Interest 
7.5.1 
Definitions of Evidence of Clinical Interest (ECI) 
Selected non-serious and SAEs can also be classified as ECI and overdose and liver toxicity ECIs must be reported as 
described in section 7.5.2. 
Events of clinical interest for this trial include: 
1. An overdose of pembrolizumab, as defined in Section 7.6 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 greater than 2X the upper limit of normal, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing. 
3. Any AEs identified in the below table 13 can be classified as immune-related events of clinical interest. A 
detailed narrative of overdose and liver toxicity ECIs should be reported as described in section 7.5.2: 
Pneumonitis  - (classified as ECI if ≥ Grade 2) 
Acute interstitial Pneumonitis 
Interstitial Lung Disease  
Pneumonitis 
Colitis  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Intestinal Obstruction 
Colitis  
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine - (classified as ECI if ≥ Grade 3 or  ≥ Grade 2 and resulting in dose modification or use of systemic steroids to 
treat the AE) 
Adrenal Insufficiency  
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine - (classified as ECI) 
Type 1 diabetes mellitus (if new onset) 
Haematologic - (classified as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to 
treat the AE) 
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 

 
 
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Hepatic  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Hepatitis 
Autoimmune hepatitis  
Transaminase elevations (ALTand/or AST) 
Infusion reactions - (classified as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome  
Serum sickness 
Infusion reactions  
Infusion-like reactions  
Neurologic - (classified as ECI for any grade) 
Autoimmune neuropathy  
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndromw 
 
 
Ocular  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Uveitis 
Iritis 
 
Renal - (classified as ECI for ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations - (classify as ECI if ≥ Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin - (classified as ECI for any grade) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (classified as ECI for ≥ Grade 3) 
Pruritus 
Rash 
Rash generalised  
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other  - (classified as ECI for any grade) 
Myocarditis 
Pancreatitis 
Percarditis 
Any other grade 3 event which is considered immune-related by the physician. 
Table 13: 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.  
7.5.2 
Reporting of ECIs 
Overdose and liver toxicity ECIs 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 e-case report forms and reported using the SAE/ECI report form within 24 hours of the 
PI/designee becoming aware of the event to the sponsor by fax 020 8915 6762 or email Pear.Trial@rmh.nhs.uk who 
will in turn notify MSD. 
 

 
 
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7.6 
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%. 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 CRF and 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 CRF 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 by Fax 020 8915 6762 or Email Pear.Trial@rmh.nhs.uk who will inform MSD. 
 
7.7 
Reporting of Pregnancy and Lactation 
Although pregnancy and lactation are not considered AEs, it is the responsibility of investigators or their designees to 
report any pregnancy or lactation in a patient (spontaneously reported to them), 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 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 still birth must be reported as SAEs (Important Medical 
Events).  If the pregnancy continues to term, the outcome (health of infant) must also be reported with the parents’ 
consent.  
Such events must be reported within 24 hours to the sponsor by Fax 020 8915 6762 or Email Pear.Trial@rmh.nhs.uk 
who will inform MSD 
 
7.8 
Definition of a Serious Adverse Reaction (SAR) 
A SAR is defined as an SAE that is judged to be related to any dose of study drug administered to the patient. 
 

 
 
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7.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) 
A SUSAR is a serious adverse reaction, the nature or severity of which is not consistent with the applicable product 
information. The IB as last amended and approved by the national competent authority serves as the reference safety 
information for the assessment of the expectedness of any adverse reaction that might occur during the clinical trial. 
7.10 
Reporting of SUSARs 
All SUSARs must be reported using the SAE report form within 24 hours of the PI/designee becoming aware of the 
event to the sponsor by fax 020 8915 6762 or email Pear.Trial@rmh.nhs.uk. The sponsor will in turn notify MSD, 
relevant Independent Ethics Committee (IEC) / Institutional review, appropriate regulatory authorities and the 
participating Principal Investigators in accordance with regulatory requirements and within the timelines as defined 
below: 
• 
For fatal and life-threatening SUSARs the sponsor should report at least the minimum information as soon as 
possible and in any case no later than seven days after being made aware of the case.  
• 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days 
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 
The Development Safety Update Report (DSUR) will be submitted annually on the anniversary of regulatory approval 
for the trial. This report will be submitted to regulatory authorities and Independent Ethics Committees (IEC) in 
accordance with all applicable global laws and regulations. Copies will be forwarded to the Sponsor, MSD 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 notification from the competent authority. However the CI/DI must notify the 
Medicines and Healthcare Products Regulations (MHRA) the Research Ethics Committee (REC) and the Sponsor of the 
new events and the measures taken and the plan for further action within 3 days of the measure being implemented.  
Should the site initiate a USM, the Investigator must inform the RM-CTU immediately either by: 
 

 
 
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Email:  
Pear.Trial@rmh.nhs.uk 
Tel:  
 
020 8915 6667 
Fax: 
 
020 8915 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 Main REC 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 Merina Ahmed 
 
Address:  
Royal Marsden NHS Foundation Trust 
 
 
 
Downs Rd 
 
 
 
Sutton 
 
 
 
SM2 5PT 
    
Tel: 
 
020 8661 3374 
 
Email:  
merina.ahmed@rmh.nhs.uk 
 
8.0 
STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The primary endpoint is the safety and tolerability of pembrolizumab in combination with RT to the lung. A standard 
3+3 dose escalation design will be used in Part A to establish the MTD of study drug when given in combination with 
RT. This will be run in two different dose RT cohorts in parallel with each other. The final review of toxicity of each 
dose level will be completed at 2 months following the final fraction of RT of the last patient in each cohort. If a DLT is 
seen in more than or equal to 2/3 patients at dose level 1, 3 patients will be recruited at dose level -1. If ≥ DLT is seen 
in no more than 1/3 patients, a further 3 patients will be recruited at dose level 1. If a DLT is seen in no more than 1/6 

 
 
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patients, proceed to the next dose level otherwise 3 patients will be recruited at dose level -1.  The same rules apply 
to the next dose level until the MTD is achieved. 
 
8.2 
Endpoints 
8.2.1 
Primary endpoints 
1. 
To establish the MTD that can be safely combined with RT to the lung in the absence of DLTs (Part A) 
2. 
To measure the toxicity rate of DLTs assessed at 2 months following final fraction of RT (Part A) 
 
The toxicity rate will be stated as the proportion of patients who have had a DLT calculated with a 95% confidence 
interval. Other toxicities will be tabulated with the proportions and frequencies of all grades described. 
Tolerability will be assessed by recording toxicity. Acute and late toxicity data will be tabulated by grade. Number and 
proportion of toxicity grades 1-4 and grade 3-4 will be reported. Toxicity data should include AEs, laboratory values, 
spirometry data, vital signs and irAEs.  
 
Toxicity rates will be reported for both RT arms, respectively. 
 
8.2.2 Secondary endpoints 
1. 
To measure the PFS and OS at 6 months and 1 year. (Part A and B) 
2. 
To measure PFS and OS in PD-L1 strong population at 6 months and 1 year. (Part A and B) 
3. 
To measure the duration of clinical benefit using RECIST v1.1 including the different RR between squamous and 
non-squamous sub-types at 6 months and 1 year. (Part A and B) 
 
Progression-free survival (PFS) will be measured from the start of RT until radiological or clinical evidence of 
progression or death and will be censored at date of last follow-up for surviving patients. 
Overall survival (OS) will be measured from the start of RT until death and will be censored at date of last follow-up 
for surviving patients.  
 
Median PFS and OS will be calculated using Kaplan-Meier methods giving associated 95% confidence intervals, 
respectively. 
 
The duration of clinical benefit (CR/PR/SD) assessed by the investigator using RECIST v1.1 will be calculated using 
Kaplan-Meier methods. 

 
 
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Differential response rates will be calculated as proportions and compared in the high and low RT arms, in the 
squamous and non-squamous cell histological sub-types, and the PD-L1 strong and non-strong, respectively, giving 
associated 95% confidence intervals.  
 
The first response assessment occurs at cycle 2, which is approximately 5 weeks following RT and will be used to 
document initial RT response. A subsequent scan at cycle 5 will document the RT response. Thereafter scans are 
performed every 3 cycles (every 9 weeks) for the first 6 months (± 7 days) then every 12 weeks after 6 months. 
Efficacy will be evaluated separately in each RT cohort. Proportions will be compared using the Chi Squared test for 
proportions or for small expected frequencies Fisher’s exact test as appropriate. 
 
 
8.2.3 
Exploratory analyses 
1. To evaluate the abscopal effect of pembrolizumab and RT. (Part A and B) 
2. Characterisation of TILs and tumour antigens in the tumour biopsies. These IHC analyses will include, but not 
necessarily be limited to, the following markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. (Part A and B) 
3. Analysis of research bloods for ctDNA. 
 
The abscopal response rate will be calculated as the proportion with the appropriate 95% confidence interval. 
Abscopal responses will only be evaluated on the scans acquired at cycle 2 and cycle 5.  
 
The effect of PD-L1 expression on response rate will be measured using the proportion of patients recorded to 
be strong expression and tested using a Chi Squared test for proportions on expression level between responders 
and non-responders. 
8.2.4 
Sample Size 
The is a 3+3 design in two RT dose cohorts each with 2 pembrolizumab dose levels (1 & 2) and the first 3 patients are 
recruited at dose level 1 in each cohort. This means that there will be a minimum of 6 and maximum of 12 patients in 
each cohort. This will give a total minimum of 12 and a maximum of 24 patients in the dose escalation phase. The 
expansion phase will then include an additional 12 patients receiving high dose RT only. The expansion cohort will 
NOT be enriched for PD-L1 strong patients.  
 

 
 
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8.2.5 
Data analysis 
All data will be analysed using the statistical software STATA version 13. Quantitative data will be presented as 
number of observations, means, standard deviations, minimum and maximum values. Categorical data will be 
presented as frequencies and proportions. When appropriate, data will be presented with 95% confidence intervals. 
Baseline characteristics will be summarised for all enrolled patients. Treatment administrations will be described for 
all cycles. Dose administration, dose modifications or delays and duration of therapy will be described. 
 
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 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
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 RM/ICR 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 IEC approval 
may be implemented only after a copy of the IEC/IRB’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 
IEC/IRB approval. However, in this case, approval must be obtained as soon as possible after implementation. 

 
 
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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 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) 

 
 
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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 IEC/IRB will be provided by the Sponsor to all 
participating sites. 
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 of 1998.  On the CRFs or other documents submitted to the RM-CTU, patients should be identified by 
their initials and a patient study number only.  
 
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.  
 
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 CRF, taking into account data protection regulations. The clinical data should be recorded in the CRF and the 
following must be verifiable by the source data: patient consent, medical history, patient’s eligibility for participation 
in the trial, study treatment administration (pembrolizumab and RT), routine haematology and biochemistry and 
response to treatment. 
 

 
 
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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 or personal information 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  
• 
sufficient data is recorded for all participating patients to enable accurate linkage between hospital records 
and 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 

 
 
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All 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 data 
relating to protocol procedures, IMP administration, laboratory data, safety data and efficacy data into the CRF.  
10.4 
Recording of Data 
Patients’ data will be recorded on a trial specific CRF designed by RM-CTU. Upon signing the informed consent form, 
the patient is assigned to the next sequential patient trial identification number available. To ensure recruitment is 
not delayed in any way a paper CRF will be available for use in the event that the electronic CRF is not ready for use.  
 
The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the data reported in 
the 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 CRFs.  All protocol required 
investigations must be reported in the 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 CRF.  
 
Authorised site personnel must not enter study-specific data directly into CRFs and must ensure all results are 
appropriately documented in the patients’ medical records. The CRF will be signed by the Investigator or by an 
authorised staff member. Study specific information will be entered into a CRF visit by visit. Data that are derived 
should be consistent with the source documents or the discrepancies should be explained. All CRF data should be 
anonymous, i.e. identified by study patient number only. 
 
Once the patient is ‘off study’ and the CRF has been fully completed, the Investigator must provide a signature to 
authorise the complete patient data. 
 
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 

 
 
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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 
10.6.1 Delegations of Responsibilities 
This trial is sponsored by the Royal Marsden NHS Foundation Trust.  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: 
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.  
• 
Raising and resolving queries with local investigators. 
• 
Keeping records of all SAEs, overdose incidents, pregnancies and overdose and liver toxicity ECIs reported by 
investigators. 
• 
Notifying the Main REC, MHRA and Investigators of related SAEs.  
 
MSD 
• Provision of pembrolizumab 
 
Participating Sites 
• 
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) and ensuring appropriate 
archiving of documentation once the trial has ended. 
• 
Taking appropriate urgent safety measures. 
• 
Centres wishing to recruit to this study will be asked to provide evidence that they can deliver protocol 
treatment.  

 
 
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• 
Responsibilities are defined in an agreement between an individual participating centre and RM-CTU, which 
must be signed and in place before recruitment can commence.  
 
10.7 
Protocol compliance and amendments 
All participating sites will be required to sign an agreement with RM-CTU that 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 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. 
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 (1 per study) 
A Trial Management Group (TMG) will be set up and membership will include Chief Investigator, Co-Investigators, 
Trial Statistician and Trial Manager. Principal Investigators and other key study personnel will be invited to join the 
TMG as appropriate. The TMG has operational responsibility for the conduct of the trial. The TMG is bound to act on 
the advice of the PPSRC but is also responsible for monitoring recruitment, safety and governance of the trial as well 
as collaborating with subsequent translational sub-studies. The TMG will also review any safety concerns and can 
convene a meeting of the PPSRC if significant concerns exist. The TMG will meet weekly to review results and side 
effects of all patients in the PEAR study. The statistician may not be required at every meeting but should be called 
upon if necessary. The format of this meeting will be concordant with that used for Phase I studies at RMH. 
10.8.2 Pembrolizumab Project Safety Review Committee (PPSRC) 
PPSRC has been established to coordinate the management and governance of 4 phase 1 trials evaluating 
Pembrolizumab in combination with standard of care RT in different tumour types (bladder, cervix, head and neck, or 
lung).  The PPSRC will include the chief investigators of all 4 Pembrolizumab trials (Dr Tree, Professor Harrington, Dr 

 
 
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Lalondrelle and Dr Ahmed), Dr James Larkin, Representative from RM-Clinical Trials Unit, Senior Statistician and be 
chaired by a clinician independent of study investigators.  The PPSRC will meet monthly and at every dose escalation 
point, the meeting frequency maybe decreased during the expansion phases of all the studies if considered safe to do 
so. The role of the PPSRC is: 
• 
Review relevant safety data and make dose escalation decisions for all studies 
• 
Reviews all SAEs and emerging safety data both from RM Sponsored studies and external SUSARS received 
from MSD 
• 
Monitor progress of the trials and ensure emerging safety information is evaluated and protocol and GCP 
principles are adhered to.  
The PPSRC terms of reference, roles and responsibilities will be defined in a charter.  Further internal or external 
experts may be consulted 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 (for example clinic visits 
on Sundays). 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. 

 
 
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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. 
 
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 circulated 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. 

 
 
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11.0 
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12.0 
APPENDICES 
12.1 
Appendix 1: 
Patients will be treated with external beam RT using a linear accelerator with photon energy of 4-15 MV. A standard 
non-contrast planning CT thorax will be obtained with 2-3mm slice thickness from cricoid cartilage to below 
diaphragm. If supraclavicular disease is being treated the CT scan will extend up to mastoid. The gross tumour volume 
is determined from CT and/or PET scans. PTV incorporates the GTV with a 1.5 to 2cm margin. Field margin will be 
defined using standard RMH criteria.  
 
If the field size is > 12cm X 12cm equivalent square, consider using low dose fractionation or excluding disease from 
the field . Any thoracic disease out of field should be documented and can be used to assess abscopal response. 
Alternatively if lung constraints are maintained then high dose fractionation can be used with a larger field size, 
Planning will be in accordance with RMH protocols for palliative planning of lung tumours, ensuring that there are no 
hotspots over cord > 105% for the 36Gy dose fractionation. 
 
In general, parallel-opposed (AP-PA) fields can be used. Isodose intervention should be considered for 36Gy in 12 
fractions. If it is anticipated that parallel-opposed fields will lead to severe toxicity, a conformal plan using planning 
CT-scan is indicated to keep the V20 (EQD2) below 35%. Mean lung dose should be maintained at an EQD2 of ≤ 18Gy. 
In all treatment planning, lung correction is required. Dose will be prescribed at the midpoint or at 100% as per ICRU 
guidelines. 
 
3D dose-volume information for the tumour and the normal tissues will be obtained for subsequent analysis. The 
following  normal tissues should be contoured: lung,  heart, spinal cord and oesophagus. 
 
Lung V20, Mean Lung Dose in EQD2 should be obtained for all patients. Dose volume histogram data will be obtained 
for heart, lungs oesophagus and spinal cord. The length of oesophagus in high dose radiotherapy field will be 
documented.  
 
Verification will proceed in accordance with RMH RT department’s standard policies. 
 

 
 
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12.2 
Appendix 2: 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) 
 
12.3 
Appendix 3: LENT SOMA Scales for all Anatomical Sites 
This study will utilise 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 LENT SOMA scoring 
system. 
 
12.4 
Appendix 4: Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumours 
RECIST version 1.1 (50) will be used in this study for assessment of tumour response. While either MRI or 
PET-CT may be utilised, as per RECIST v1.1, MRI is the preferred imaging technique in this study. 
 
12.5 
Appendix 5: Identification, Evaluation and Management of irECIs.  
NOTE: ECIs that are thought to be related to an overdose should be reported to the sponsor within 24 
hours, as described in Section 7.5.2.  
ECI 
Grade 
Action to be taken 
Supportive Care 
Pneumonitis –  
 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Consider bronchoscopy and 
biopsy/BAL, ID Consult and 
frequent chest x-ray for 
monitoring. 
• 
Conduct in person 
evaluation twice a week 
• 
1-2mg/kg/day prednisone or equivalent.  
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to 10mg prednisone 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
• 
Discontinue pembrolizumab 
• 
Hospitalise patient  
• 
Bronchoscopy with biopsy 
and/or BAL is 
recommended. 
 
• 
methylprednisolone 125mg IV.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks 
o 
Prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours  
• 
If IV steroids do not reduce initial symptoms 
within 48-72 hours treat with additional anti-
inflammatory measures. At symptom relief 

 
 
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discontinue anti-inflammatory and start 
steroid taper over 45-60 days. If symptoms 
worsen during this period refer to Section 6 
and 7. 
• 
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) 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Symptomatic treatment 
o 
Consider GI consult & 
endoscopy to rule 
out colitis 
• 
Prednisone 1-2mg/kg/day or equivalent 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to 10mg or less of 
prednisone or equivalent per days within 12 
weeks. 
• 
If symptoms worsen or persist >1 week treat 
as grade 3. 
Grade 3 
• 
Withhold pembrolizumab 
• 
Rule out bowel perforation 
• 
Recommend 
gastroenterologist consult 
&biopsy with endoscopy 
 
• 
methylprednisolone 125mg IV followed by 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less 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 Section 6 
and 7. 
Grade 4 
• 
Discontinue pembrolizumab 
• 
Manage as per grade 3 
Endocrine 
– 
Hypo 
and hyperthyroidism 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 
2 
Hyperthyroidism  
and Grade 2- 4 
Hypothyroidism 
• 
Monitor thyroid function 
until returned to baseline. 
• 
Consider consultation with 
endocrinologist. 
• 
Pembrolizumab can 
continue while on this 
treatment. 
• 
Thyroid hormone and/or steroid replacement 
therapy. 
• 
Hyper – non-selective beta blockers for initial 
therapy  
• 
Hypo – thyroid hormone replacement therapy 
as per standard of care. 

 
 
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Grade 
3 
Hyperthyroidism 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Rule out infection and 
sepsis. 
• 
IV methylprednisone 1-2mg/kg followed by 
prednisone 1-2mg/kg per day.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. Replacement 
of appropriate hormones may be required. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 
4 
Hyperthyroidism 
• 
Discontinue pembrolizumab 
• 
Manage as per grade 3 
Endocrine 
– 
Hypophysitis or other 
symptomatic 
endocrinopathy 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 – 4  
• 
Withhold pembrolizumab 
• 
Rule out infection and 
sepsis. 
• 
Monitor thyroid function 
until returned to baseline. 
• 
Consider pituitary gland 
imaging  
• 
Hypophysitis with clinically 
significant adrenal 
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 
• 
Hold pembrolizumab if new 
onset of diabetes or grade 
3-4 hyperglycaemia with 
evidence of beta cell 
failure. 
• 
Consultation with 
endocrinologist  
• 
Consider islet cell 
antibodies and antibodies 
to GAD, IA-2 ZnT8 and 
insulin. 
• 
Insulin replacement therapy is recommended 
for Type I diabetes mellitus and for Grade 3-
4hyperglycaemia associated with metabolic 
acidosis or ketonuria. 
• 
Evaluate patients with serum glucose and a 
metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide. 
Haematologic 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 

 
 
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Grade 2 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Consider Haematology 
consultation 
• 
Prednisone 1-2mg/kg daily 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 
• 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
• 
Recommend Haematology 
consultation 
• 
IV methlyprednisone 125mg or Prednisone 1-
2mg/kg p.o. (or equivalent) as appropriate. 
• 
Permanently discontinue pembrolizumab is if 
corticosteroid dose cannot be reduced to 
prednisone 10mg or less or equivalent per 
day within 12 weeks. 
Grade 4 
• 
Discontinue pembrolizumab 
• 
Recommend Haematology 
consultation 
• 
IV methlyprednisone 125mg or Prednisone 1-
2mg/kg p.o. (or equivalent) as appropriate. 
Hepatic 
– 
Drug 
induced Liver Injury 
(DILI).  
Please 
refer 
to 
Section 6 and 7 for 
definitions of (DILI) 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Report liver toxicity ECIs 
within 24 hours, as detailed 
in Section 7.5.2. 
• 
Withhold Pembrolizumab if 
AST or ALT >3.0 to 5.0 X 
ULN and/or total bilirubin is 
>1.5to 3.0 X ULN 
• 
Monitoring Liver function 
until values return to 
baseline 
• 
0.5-1mg/kg/day methlyprednisone 125mg or 
oral equivalent. 
• 
LFT grade 1 or less initiate steroid taper for no 
less than 4 weeks. Consider prophylactic 
antibiotics and resume pembrolizumab.  
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
• 
Permanently discontinue pembrolizumab for 
patients with liver mets who begin treatment 
with grade 2 elevation of AST or ALT and AST 
or ALT increase ≥50% relative to baseline and 
lasts ≥ 1 week. 
Grade 3 
• 
Report liver toxicity ECIs 
within 24 hours, as detailed 
in Section 7.5.2. 
• 
Discontinue pembrolizumab 
if AST or ALT > 5.0 X ULN 
and/or total bilirubin is >3.0 
X ULN 
• 
Consider consultation and 
biopsy to establish 
aetiology  
• 
High dose IV glucocorticosteroids for 24-
48hours.  
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks 
o 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours.  
• 
If serum transaminase levels do not decrease 
or symptoms worsen please refer to Section 6 
and 7. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
• 
Report liver toxicity ECIs 
within 24 hours, as detailed 
in Section 7.5.2. 
• 
Discontinue pembrolizumab 
• 
Manage as per grade 3 
Neurologic 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 

 
 
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Grade 2 
• 
Consider withholding 
pembrolizumab 
• 
Consider Neurology consult 
and biopsy for diagnosis. 
• 
Consider 1-2mg/kg daily of prednisone as 
appropriate 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
• 
Discontinue pembrolizumab 
• 
Obtain Neurology 
consultation  
• 
Consider biopsy for 
diagnosis. 
• 
1-2mg/kg daily of prednisone or equivalent. 
• 
If condition worsens consider IVIG or other 
immunosuppressive therapies  
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks.  
Ocular 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Evaluation by 
ophthalmologist 
recommended  
• 
Topical steroids – 1%prednisolone acetate 
suspension and iridocyclitics 
• 
Permanently discontinue IF symptoms persist 
despite treatment. 
Grade 3 
• 
Evaluation by 
ophthalmologist 
recommended 
• 
Withhold pembrolizumab & 
consider discontinuation. 
• 
1-2mg/kg of prednisone daily. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
• 
Evaluation by 
ophthalmologist 
recommended 
• 
Permanently discontinue 
pembrolizumab  
Manage as per grade 3 
Renal 
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Withhold Pembrolizumab 
• 
1-2mg/kg of prednisone daily. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
• 
Discontinue Pembrolizumab 
• 
Renal consultation and 
biopsy as appropriate 
• 
1-2mg/kg of prednisone daily. 
• 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
Skin 
– 
Rash 
and 
pruritus  
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Symptomatic treatment 
• 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics 
• 
Treatment with oral steroids at PIs discretion 
Grade 3 
• 
Withhold Pembrolizumab 
• 
Consider dermatology 
consult & biopsy for 
diagnosis. 
• 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xdaily 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
• 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
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100                                                                
 
Grade 4 
• 
Discontinue pembrolizumab 
• 
Dermatology consultation  
• 
Consider biopsy for 
diagnosis & clinical 
photographs 
• 
Initiate steroids starting with 1-2mg/kg 
prednisone or equivalent.. 
• 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
Skin – Dermatitis 
exfoliative, 
erythemamulitforme, 
Stevens Johnson 
syndrome§, toxic 
epidermal 
necrolysis§. 
§ If it is suspected 
that the patient has 
SJS or TEN, 
pembrolizumab 
should be withheld. 
The patient should 
be referred to a 
dermatologist for 
management. If SJS 
and TEN is 
confirmed, then 
pembrolizumab 
should be 
permanently 
discontinued.”   
Grade 
1 
(Asymptomatic) 
• No action 
• Intervention not indicated 
Grade 2 
• 
Symptomatic treatment 
• 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics. Treatment with oral steroids at 
PIs discretion 
Grade 3 
• 
 
• 
Withhold Pembrolizumab 
• 
Consider dermatology 
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 
• 
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 
¶”Ensure that other 
causes of myocarditis 
are 
adequately 
evaluated to exclude 
other aetiologies 
Grade 
2 
or 
Grade 1 that do 
not 
improve 
with 
symptomatic 
treatment. 
• 
Withhold Pembrolizumab 
• 
Consider biopsy for 
confirmation of diagnosis. 
• 
Systemic corticosteroids may be indicated. 
• 
If so: 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
• 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks. Otherwise, Pembrolizumab treatment 
may be restarted and the dose modified as 
specified in the protocol 
Grade 3 
• 
Withhold Pembrolizumab 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
• 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 

 
 
The PEAR Study Clinical Study Protocol v5.1 19.06.2020CCR 4282                                                        Confidential                                   
EudraCT No: 2014-005673-36 ClinicalTrials.gov Id: NCT02587455                                                                       Page 100 of 
100                                                                
 
weeks. Otherwise, Pembrolizumab treatment 
may be restarted and the dose modified as 
specified in the protocol 
Grade 4 
• 
Discontinue Pembrolizumab 
• 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
 
 
12.6 
Appendix 6: MRC Dyspnea Scale 
Grade 
Description 
0 
Climbs hills or stairs without dyspnoea 
1 
Walks any distance on flat without dyspnoea 
2 
Walks over 100 yards without dyspnoea 
3 
Dyspnoea on walking 100 yards or less 
4 
Dyspnoea on mild exertion, e.g. undressing 
5 
Dyspnoea at rest 
As published: Bleehen et al. A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate 
and vincristine or six courses of etoposide and ifosfamide in SCLC: Survival and prognostic factors. Medical Research 
Council Lung Cancer Working Party Br J Cancer 1993; 68(6): 11506. (59)