A Phase II Trial of Pembrolizumab in Patients With Non-small Cell Lung Cancer and a Performance Status of 2
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: University of Birmingham

 
 
 
 
 
 
A phase II trial of pembrolizumab in 
patients with non-small cell lung cancer 
and a performance status of 2 
 
 
PROTOCOL version 6.0, 10th July 2018 
 
 
 
 
 
 
 
 
 
 
EudraCT Number: 
2015-002241-55 
Sponsor Number: 
RG_14-172 
CRCTU Number:  
LU2008 
ISRCTN: 
10047797 
ClinicalTrials.gov: 
NCT02733159 
 

 
 
Page ii 
PePS2 version 6.0_10-Jul-2018 
 
TRIAL CONTACTS 
 
Chief Investigator: 
Professor Gary Middleton, Professor of Medical Oncology 
Institute of Immunology and Immunotherapy, University of Birmingham. 
Tel: 0121 627 2000 
 
Clinical Coordinators: 
Professor Christian Ottensmeier, Professor of Experimental Medicine 
University of Southampton and Southampton University Hospitals 
Tel: 0238 120 5161 (PA, Miss Lynsey Block) Mobile 07879485676 
Dr Yvonne Summers, Consultant Medical Oncologist 
The Christie and University Hospital South Manchester 
Tel: Christie 0161 446 8016; UHSM 0161 291 2829; Mobile 07776 144513 
Dr Alastair Greystoke, Senior Lecturer and Honorary Consultant in Medical Oncology, 
Sir Bobby Robson Clinical Trials Unit Freeman Hospital Newcastle upon Tyne 
Tel: 0191 213 9224 or 0191 213 8476; Mobile 07738719014 
 
Lead Biostatistician: 
Professor Lucinda Billingham, Professor of Biostatistics, Cancer Research UK Clinical Trials 
Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, B15 
2TT 
 
Trial Statistician: 
Mr Kristian Brock, Senior Statistician, CRCTU, University of Birmingham. 
 
Trial Coordinator: 
Mr Rhys Mant, Early Drug Development (EDD) Team, CRCTU, University of Birmingham. 
 
Senior Trial Manager: 
Dr Joshua Savage, EDD Team Leader, CRCTU, University of Birmingham. 
PePS2 Trial Office 
Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, 
University of Birmingham, Edgbaston, Birmingham. B15 2TT 
Enquiries: 
 0121 414 6788 
 0121 414 3529 
 PePS2@trials.bham.ac.uk 
Registration: 
 0121 414 6788 or 6754 
(9.00 am till 5.00 pm Monday to Friday) 
Serious Adverse Event Reporting: 
 0121 414 3529 (primary) 
 0121 414 7989 (secondary) 
 
Sponsor: 
University of Birmingham 
 

 
 
Page iv 
PePS2 version 6.0_10-Jul-2018 
 
AMENDMENTS 
 
The following amendments and/or administrative changes have been made to this protocol 
since the last submission. 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
1 
07-Mar-2016 
2.0 
Substantial 
amendment 
• Updated contact details 
• Addition of Safety follow-up visits to 
schedule of events, for 6 months 
after the last study dose. 
• Removal of Autoantibody collection 
from Schedule of Events 
• Statistical section has been redrafted 
for clarity 
• Correction of grammatical, 
formatting/ spelling errors 
• Addition of Safety follow-up visits in 
Sections 6.8: patient follow up, 6.11.3 
Reporting requirements and 6.12.1.3 
Events of Clinical Interest for 6 
months after the last study dose. 
 
07-Jun-2016 
2.0a 
Non 
substantial 
amendment 
• Stool sample instead of rectal swab 
• Correction of formatting and 
grammatical errors 
2 
30-Jan-2017 
3.0 
Substantial 
amendment 
• Updated contact details 
• Correction of formatting and 
grammatical errors throughout 
• Eligibility: Updated Performance 
Status criterion 
• Clarified procedure for pre-
registration screening 
• Eligibility: Amended requirements for 
obtainingPD-L1 status from archival 
tissue or a new biopsy if archival 
tissue is unavailable 
• Clarified patients with both PD-L1 
positive and negative tumours are 
eligible. Patients who have had 
systemic therapy since the biopsy do 
not need to have a repeat biopsy. 
• Added that a newly obtained biopsy 
is mandatory at baseline (prior to 
Cycle 1/Day 1) for the assignment of 
PD-L1 status if an archival biopsy is 
not available and/or PD-L1 testing on 
the archival tissue is unsuccessful 
(see section 4.1 for more details). 
• Added slides of fresh cut sections 
from Formaldehyde Fixed Paraffin 
Embedded (FFPE) tissue block will 

 
 
Page v 
PePS2 version 6.0_10-Jul-2018 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
be assessed by the site Pathologist 
for PD-L1 testing 
• Added if the PD-L1 status has 
already been obtained from a 
nationally recognised and MSD-
approved laboratory, this will be 
acceptable and repeat PD-L1 
staining will not be required 
• Added if a patient has had a repeat 
biopsy for the purpose of PD-L1 
staining for the PePS2 trial but the 
biopsy failed to yield sufficient cells 
for PD-L1 status, this patient will still 
be eligible to enter the PePS2 trial 
but will be categorised as PD-L1 non-
evaluable. 
• Added clearer definition of 
performance status of 2 in the 
inclusion and exclusion criteria. 
• Added flow chart of Treatment 
Assessments 
• Clarified assessments performed up 
to 28 and 7 days before treatment 
• Clarified procedure for registration 
• Added table for frequency of sample 
collection 
• Investigator brochure changed to 
Summary of Product Characteristics 
• Added another Event of Clinical 
interest and reference to immune-
mediated AEs 
• Statistical considerations re-written 
and dose reduction removed. 
5 
14-Jun-2017 
4.0 
Substantial 
amendment 
• Clarified trial objectives, outcomes 
measures and exclusion criteria in 
trial synopsis 
• Timing of some of the screening and 
week 0 assessments changed. 
• Additional measurments for cortisol 
and CRP added plus smoking 
history. 
• Clarified amount of time blood 
pressure and ECG to be performed. 
• To routine laboratory tests table 
added CRP and cortisol 
measurements and amended 
urinalysis. 
• Abbreviations table updated 
• Background and Rationale updated 

 
 
Page vi 
PePS2 version 6.0_10-Jul-2018 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment 
Summary of amendment 
• Updated objectives and outcome 
measures, clarifying and sumarising 
primary objectives and secondary 
and exploratory outcome measures 
• Updated Trial Design 
• Amended Inclusion and Exclusion 
criteria 
• Amended Patient Registration to 
receive a copy of the ICF 
• Treatment assessments updated to 
reflect changes in addition of and 
time when samples collected. 
• Updated Dose Modification and 
Toxicity Management section 
• Changed prohibited concomitant 
medications so that systemic steroids 
can be taken by patients have started 
trial treatment but steroids can only 
be taken for a maximum of 2 weeks 
• Added patients who meet RECIST 
criteria for progressive disease (PD) 
may be continued on trial treatment if 
the treatment is tolerable and 
believed to be of clinical benefit to 
Patient Withdrawal section. 
• During reporting period, only details 
of all treatment-related AEs will be 
documented. 
• Amended Dose Modification and 
toxicity management section 
• Amended pembrolizumab Infusion 
Reaction Dose modification and 
Treatment Guidelines table 
• Amended Statistical Considerations 
section 
6 
14th August 
2017 
5.0 
Substantial 
amendment 
• Updated contact details 
• Specified instructions for collection 
and freezing of stool sample. 
• Correction of formatting errors 
7 
10-Jul-2018 
6.0 
Substantial 
amendment 
• Trial contact details updated. 
• Table 4 updated. 
• Section 15: Regualtory framework 
updated. 
• Section 16: Updated to include 
General Data Protection Regulations. 
• Minor spelling and formatting 
changes throughout. 
 
 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
TRIAL SYNOPSIS 
Title 
PePS2: A phase II trial of pembrolizumab in patients with non-small cell lung cancer and a 
performance status of 2 
Trial Design 
Multi-centre, single-arm phase II trial, testing pembrolizumab in a population of patients with 
non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) 
performance status of 2 
Trial Objectives 
This is a phase II trial of programmed cell death protein 1 (PD-1) blockade in patients with 
programmed death ligand 1 (PD-L1) defined NSCLC and an ECOG performance status of 2 
with the primary purposes: 
• To determine that pembrolizumab is safe and tolerable at the selected dose 
• To detect the durable clinical benefit in this population of patients treated with 
pembrolizumab that would justify further investigation 
 
Secondary objective: 
• To measure patient health related quality of life (HRQoL) 
 
Exploratory objective: 
• To discover possible biomarkers to predict for a response to pembrolizumab 
Outcome Measures 
Primary outcome measures: 
• Toxicity defined as the occurrence of a treatment-related dose delay or treatment 
discontinuation due to an adverse event 
• Durable Clinical Benefit defined as the occurrence of a complete response (CR), partial 
response (PR) or stable disease (SD) without prior progressive disease (PD) at or after 
the second scheduled CT scan (scheduled to occur at18 weeks). 
 
Secondary outcome measures: 
• Objective Response (OR) 
• Progression-free survival time (PFS) 
• Time to Progression (TTP) 
• Overall survival time (OS) 
• Health related quality of life (HRQoL) 
• Duration of objective response (DOR) and duration of stable disease (DSD) 
Patient Population 
Patients with non-small cell lung cancer and an ECOG performance status of 2 (Appendix 1) 
Sample Size 
60 patients 
Inclusion Criteria (not exhaustive - refer to section 4) 
• Histologically confirmed PD-L1 status defined NSCLC. 
• ECOG performance status 2 with no deterioration over the previous 2 weeks assessed 
by consenting physician. 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
o Patients must be ambulatory and capable of all self-care but unable to carry out any 
work activities 
o Patients must be up and about more than 50% of waking hours 
• Life expectancy > 12 weeks. 
• Uni-dimensionally measurable disease according to Response Evaluation Criteria in 
Solid Tumours (RECIST) v1.1 (Appendix 2). 
• Computerised Tomography (CT) scan of chest and abdomen within 28 days of starting 
pembrolizumab. 
• Adequate haematological function: 
o Platelet count ≥100 x 109 /L 
o Neutrophils ≥1.5 x 109/L 
o Haemoglobin ≥ 90 g/L 
• Adequate hepatic function: 
o Serum bilirubin ≤1.5 x upper limit of normal (ULN) 
o Serum transaminases ≤2.5 x ULN 
• Adequate renal function 
o Creatinine clearance <1.5 times ULN concurrent with creatinine clearance >50 
ml/min (calculated by Cockcroft and Gault equation – see Appendix 3). If this is ≤ 50 
ml/min then an isotopic Glomerular Filtration Rate (GFR) may be carried out and 
must be > 50 ml/min 
• Provision of signed and dated, written informed consent prior to any trial specific 
procedures, sampling and analyses. 
Exclusion Criteria (not exhaustive - refer to section 4) 
• Patients who do not meet the criteria of performance status = 2 on the ECOG 
Performance scale (Appendix 1), i.e. patients should not be:- 
o ambulatory and able to carry out work of a light or sedentary nature e.g. light house 
work, office work. 
• Untreated symptomatic brain or leptomeningeal metastatic disease. 
• Medical or psychiatric conditions comprising informed consent. 
• Any medical condition which in the opinion of the Investigator would compromise the 
ability of the patient to participate in the trial or which would jeopardise compliance with 
the protocol. 
• Radiotherapy within 28 days of trial treatment. 
• Active autoimmune disease that has required systemic treatment in past 2 years. 
• Chronic usage of steroids or other immunosuppressant medication. 
• Previous history of pneumonitis. 
• Any evidence of clinical autoimmunity. 
Trial Duration 
4 years (1 year recruitment, 2 years trial treatment, 1 year patient follow up) 
Trial Office Contact Details 
PePS2 Trial Office 
Cancer Research UK Clinical Trials Unit,Institute of Cancer and Genomic Sciences 
University of Birmingham,Edgbaston,Birmingham,B15 2TT 
 
Phone: 0121 414 6788 
Fax: 
0121 414 3529 
E-mail: PePS2@trials.bham.ac.uk 
 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Trial Schema 
 
Treatment Assessments 
CT Scans: every 9 weeks until disease progression 
Safety Assessments, Toxicity Assessment and Health Related Quality of Life Questionnaires: every 3 weeks, first day of 
every cycle until end of treatment 
Register Patient 
Call CRCTU  0121 414 6788 or 6754 (Monday to Friday, 9am to 5pm) 
Treatment (n=60) 
Treatment for 2 years, or until progression or unacceptable toxicity, 
pembrolizumab, every 3 weeks, 200 mg IV 
Post Treatment Assessments 
Every 4 weeks for 6 months, then 12 weekly until death 
Survival status, treatment after progression 
Enrolment - within 7 days of treatment 
All patients: physical exam, weight, height, vital signs, ECOG, bloods 
(biochemistry & haematology), Pregnancy test, urinalysis, renal function, 
Charlson Index, AEs/Concomitant medication 
Excluded if: 
• Do not meet eligibility criteria 
• Decline to participate 
Enrolment - within 28 days of treatment 
All patients: medical history, prior medications, ECOG, coagulation 
parameters, CT scan (Chest, Abdomen) 
Pregnancy test, HIV, hepatitis B and C, ECG 
Excluded if: 
• Do not meet eligibility criteria 
• Decline to participate 
Recruitment from Thoracic Oncology Clinic 
First line NSCLC patients with an ECOG 
performance status of 2 
Any other line NSCLC patients with an ECOG 
performance status of 2 
Obtain consent within 28 days to start of treatment 
Pre-Registration screening 
All patients: Informed consent, 
Tumour biopsy for PD-L1 status from archival sample or from fresh tumour biopsy if PD-L1 status 
cannot be ascertained from existing tissue 
Call CRCTU  0121 414 6788 or 6754 (Mon to Fri 9am to 5pm) to give PePS2 Trial Office biopsy 
details when sending tissue for PD-L1 staining 

 
 
Page x 
PePS2 version 6.0_10-Jul-2018 
 
Table 1: Schedule of Events 
 
Screening 
Treatment 
Follow up 
Within 28 
days of 
entry 
Within 7 
days of 
treatment 
Week/Cycle (21 Days ± 3 days) 
Cycle 11-
35  
(21 Days 
± 3 Days) 
End of 
treatment 
30 day 
Follow up 
Long-term 
follow up 
Every 4 weeks 
for 6 months  
then 12 weekly 
until death 
Week (approximate) 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
N 
 
 
 
Cycle 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
N 
 
 
 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical 
History/Prior Medications2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Charlson Index3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRQoL Questionnaire4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance status6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Adverse Events and 
Concomitant Medications8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X* 
Full blood count (FBC)9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive serum 
chemistry panel9 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis9 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X* 
X 
X 
 
Coagulation parameters10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

 
 
Page xi 
PePS2 version 6.0_10-Jul-2018 
 
 
Screening 
Treatment 
Follow up 
Within 28 
days of 
entry 
Within 7 
days of 
treatment 
Week/Cycle (21 Days ± 3 days) 
Cycle 11-
35  
(21 Days 
± 3 Days) 
End of 
treatment 
30 day 
Follow up 
Long-term 
follow up 
Every 4 weeks 
for 6 months  
then 12 weekly 
until death 
Week (approximate) 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
N 
 
 
 
Cycle 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
N 
 
 
 
HIV, Hepatitis B and C11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or 
Serum β-HCG12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal function – GFR13 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function and cortisol14 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X14 
X 
X 
 
PBMC sample (60 ml blood)15 
 
 
X 
X 
X 
(10ml) 
X 
 
 
X 
(10ml) 
 
 
X 
(10ml) 
 
X 
 
 
Stool sample 16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokine/Chemokine Panel 
and proteomics17 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Germline DNA18 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ctDNA19 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Tumour Imaging with 
contrast20 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X20 
 
X20 
X20 
Study drug administration  
(30 minute infusion) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumour biopsy (if archived 
tissue not available)21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Page xii 
PePS2 version 6.0_10-Jul-2018 
 
 
Screening 
Treatment 
Follow up 
Within 28 
days of 
entry 
Within 7 
days of 
treatment 
Week/Cycle (21 Days ± 3 days) 
Cycle 11-
35  
(21 Days 
± 3 Days) 
End of 
treatment 
30 day 
Follow up 
Long-term 
follow up 
Every 4 weeks 
for 6 months  
then 12 weekly 
until death 
Week (approximate) 
 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
N 
 
 
 
Cycle 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
N 
 
 
 
Optional tumour biopsy from 
patients with durable clinical 
benefit post therapy22 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Survival assessment 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

 
 
Page xiii 
PePS2 version 6.0_10-Jul-2018 
 
1. 
Written informed consent must be obtained prior to performing any protocol specific procedure and within 28 days to starting treatment. 
Patient will need to be re-consented to PePS2 if over 28 days to treatment start. 
2. 
Includes smoking history, history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical 
treatment, and best response to prior systemic treatments. Date of last prior cancer treatment must be documented. 
3. 
For Charlson Index see Appendix 4. 
4. 
QoL questionnaires include Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire, EQ- 5D and patient generated 
subjective global assessment questionnaires, see Appendix 5. To be carried out prior to treatment. 
5. 
Vital signs to include: temperature, pulse, respiratory rate and blood pressure (average of 3 BP readings). 
6. 
For ECOG performance status criteria see Appendix 1. 
7. 
A standard 12-lead ECG will be performed, in triplicate if clinically abnormal rhythm detected, using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as it should be reported as a concurrent condition. Additional time 
points may be performed as clinically necessary. 
8. 
Adverse Events (AEs) and laboratory safety measurements will be graded per NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0, Appendix 6. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
*In addition to AE and Concomitant Medication review at each cycle, extra safety monitoring will be performed after the last trial dose 
monthly for up to 6 months. 
9. 
Routine laboratory tests (e.g., Full blood count (FBC); comprehensive serum chemistry panel; urinalysis) will be performed by the local 
trial site laboratory or their contract laboratory. Following cycle 13, urinalysis should be performed every 9 weeks*. FBC, serum 
chemistry and urinalysis may be collected up to 48 hours prior to any Cycle “X”, Day 1 dosing. Routine laboratory tests (serum 
chemistry; haematology) for screening should be performed within 7 days of first treatment. 
10. 
Prothrombin (PT) / International Normalised Ratio (INR) and partial thromboplastin (aPTT) should be collected at Screening and at the 
mandatory Safety Follow-up Visit after discontinuation of trial therapy. Coagulation parameters should be determined throughout the 
trial when clinically indicated. 
11. 
Testing will be performed by the local laboratory at Screening. Include Hepatitis C Virus (HCV) RNA (qualitative), Hepatitis B surface 
Antigen (HBsAg), and Human Immunodeficiency Virus (HIV) 1/2 antibodies. 
12. 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours of the first dose. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required. See Section 4.3 (Contraception). 
13. 
Patients must have adequate renal function as defined by Creatinine clearance <1.5 x ULN concurrent with creatinine clearance >50 
ml/min (calculated by Cockcroft and Gault equation – see Appendix 3, or as per institutional standard). If this is ≤50 ml/min then an 

 
 
Page xiv 
PePS2 version 6.0_10-Jul-2018 
 
isotopic GFR may be performed and must be ≥50 ml/min. 
14. 
Analysis of cortisol, T3, T4 and TSH (Thyroid Stimulating Hormone) will be performed by the local site laboratory. Following Cycle 2, 
testing will be performed every other cycle. 
15. 
60 ml blood collected before the start of infusion at cycle 1, cycle 2, cycle 4 and on termination of treatment and 10ml blood collected 
before the start of infusion at cycle 3, 7 and 10. Processing and storage of blood samples are to be carried out as described in the 
PePS2 Laboratory Manual. 
16. 
Collected before start of infusion 1. Processing and storage of the stool samples are to be carried out as described in Section 7.6.3. 
17. 
Collected before start of infusion at cycles 1, 4, 7, and 10. Processing and storage of blood samples are to be carried out as described 
in PePS2 Laboratory Manual. Analysis will be performed by a central laboratory. 
18. 
Collected before start of infusion at cycle 1. Analysis will be performed by a central laboratory. Informed consent for future biomedical 
research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw). This sample should only be taken once from each subject. 
19. 
Collected before start of infusion at cycles 1, 4, 7, 10 and 13 and on termination of treatment. Analysis will be performed by a central 
laboratory. Processing and storage of blood samples are to be carried out as described in PePS2 Laboratory Manual. 
20. 
Tumour imaging by CT with contrast will be performed within 28 days prior to enrolment. The same imaging technique has to be used 
in a patient throughout the trial. Scans will be reported by RECIST 1.1 (Appendix 2). 
Tumour imaging will be performed every 9 weeks whilst the patient remains on trial therapy. CT scan results must be ready prior to 
cycle 4, 7, 10 etc. to allow the treating clinician to make decision about treatment continuation. 
Follow up CT scans will only be required every 9 weeks until progression or until commencement of another cancer treatment for 
patients who come off treatment due to toxicity. Response status will be assessed by the trial site. 
21. 
A newly obtained biopsy is mandatory during screening (prior to cycle 1/day 1) for the assignment of PD-L1 status if an archival biopsy 
is not available and/or PD-L1 testing on the archival tissue is unsuccessful (see sections 4.1 and 5.2.1.1 for more details). 
The biopsy may be either Endobronchial ultrasound (EBUS) or Computer-Tomography (CT)-guided. Refer to the PePS2 Laboratory 
Manual re: PD-L1 testing. 
22. 
One optional newly obtained biopsy for patients who were initially responsive but have relapsed on treatment may be taken at the end 
of treatment. The biopsy may be either Endobronchial ultrasound (EBUS) or Computer-Tomography (CT)-guided. Specific instructions 
for tissue collection and shipment are provided in the PePS2 Laboratory Manual. 
23. 
Follow up will be completed every 4 weeks for 6 months then every 12 weeks to record treatment after progression and death date. 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Table 2: Routine Laboratory Tests 
The laboratory tests listed below will be performed only by the local study trial site laboratory. 
Patient treatment and overall management decisions will be based on local laboratory data. 
Haematology  
(Full blood count) 
Biochemistry 
Urinalysis 
Other 
Haematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Haemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate transferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Creatinine 
 Microscopic exam (If any of 
the above are abnormal) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Lactate dehydrogenase (LDH) 
Urine pregnancy test † 
Free thyroxine (T4) 
 
Calcium 
 
Thyroid stimulating hormone (TSH) 
 
Glucose 
 
HBV antibody test 
 
Phosphorus 
 
HCV RNA test 
 
Potassium  
 
HIV antibody test 
 
Sodium 
 
Blood for exploratory studies 
 
Magnesium 
 
Stool sample for evaluation of gut 
microbiome 
 
Total Bilirubin 
 
Cortisol 
 
Direct Bilirubin  
(If total bilirubin is elevated above 
the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
C-reactive protein (CRP) 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.  

 
 
Page xvi of 53 
PePS2 version 6.0_10-Jul-2018 
 
ABBREVIATIONS 
 
aPTT 
Partial Thromboplastin Time 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ABPI 
Association of the British Pharmaceutical Industry  
AST 
Aspartate Transferase 
BEBOP 
Bayesian Evaluation of Binary Outcomes with Predictive variables 
CR 
Complete Response 
CRCTU 
Cancer Research UK Clinical Trials Unit 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CRP 
C-reactive protein 
CR-UK 
Cancer Research UK 
CT 
Computerised Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumour DNA 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DKA 
Diabetic Ketoacidosis 
DoR 
Duration of Response 
DSD 
Duration of stable disease 
ECG 
Electrocardiogram 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
eQTL 
Expression Quantitative Trait Loci 
eRDC 
Electronic Remote Data Capture 
FACT-L 
Functional Assessment of Cancer Therapy - Lung 
FBC 
Full Blood Count 
FFPE 
Formaldehyde Fixed Paraffin Embedded 
FSH 
Follicle-Stimulating Hormone 
Gd 
Grade 
GFR 
Glomerular Filtration Rate 
GP 
General Practitioner 
HBsAg 
Hepatitis B surface Antigen  
HBV/HCV 
Hepatitis B/C Virus 
HRQoL 
Health Related Quality of Life 
HIV 
Human Immunodeficiency Virus 

 
 
Page xvii of 53 
PePS2 version 6.0_10-Jul-2018 
 
IB 
Investigator Brochure 
IFN 
Interferon 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
irRC 
Immune related Response Criteria 
ISF 
Investigator Site File 
ITIM 
Immunoreceptor Tyrosine-based Inhibition Motif 
ITSM 
Immunoreceptor Tyrosine based Switch Motif 
IV 
Intravenous 
KCO 
Reduced transfer coefficient 
LDH 
Lactate Dehydrogenase 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MD-PS 
Doctor assessed – Performance Status 
MDSC 
Myeloid-Derived Suppressor Cell 
mOS 
Median Overall Survival 
NIHR 
National Institute for Health Research 
NK 
Natural Killer 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Objective Response  
OS 
Overall Survival Time 
OTC 
Over The Counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease  
PD-1 
Programmed cell Death protein 1 
PD-L1 
Programmed cell Death Ligand 1 
PD-L2 
Programmed cell Death Ligand 2 
PFS 
Progression Free Survival time 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin 
REC 
Research Ethics Committee 
RECIST 
Response Evaluable Criteria in Solid Tumours 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SAR 
Serious Adverse Reaction  
SD 
Stable Disease 

 
 
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SJS 
Stevens-Johnson Syndrome 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 Diabetes Mellitus 
T3 
Total Thriiodothyronine 
T4 
Free Thyroxine 
TEN 
Toxic epidermal necrolysis 
TIL 
Tumour infiltrating lymphocyte 
TNO 
Patient Trial Number 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to Progression 

 
 
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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE .............................................................................................................. 1 
1.1 
BACKGROUND ............................................................................................................................................ 1 
 
Pharmaceutical and Therapeutic Background .................................................................................. 1 
1.1.1
 
Pembrolizumab in Lung Cancer ......................................................................................................... 2 
1.1.2
1.2 
TRIAL RATIONALE ....................................................................................................................................... 2 
 
Rationale for Patient Population ....................................................................................................... 2 
1.2.1
 
Rationale for Design .......................................................................................................................... 3 
1.2.2
 
Rationale for Choice of Treatment .................................................................................................... 4 
1.2.3
2 
OBJECTIVES AND OUTCOME MEASURES .................................................................................................. 4 
2.1 
OBJECTIVES ............................................................................................................................................... 4 
 
Primary Objectives ............................................................................................................................ 4 
2.1.1
 
Secondary Objectives ........................................................................................................................ 4 
2.1.2
 
Exploratory Objectives....................................................................................................................... 4 
2.1.3
2.2 
OUTCOME MEASURES ................................................................................................................................. 4 
 
Primary Outcome Measures .............................................................................................................. 5 
2.2.1
 
Secondary Outcome Measures .......................................................................................................... 5 
2.2.2
3 
TRIAL DESIGN ........................................................................................................................................... 6 
4 
ELIGIBILITY ............................................................................................................................................... 6 
4.1 
INCLUSION CRITERIA .................................................................................................................................... 6 
4.2 
EXCLUSION CRITERIA ................................................................................................................................... 7 
4.3 
CONTRACEPTION ........................................................................................................................................ 8 
 
Women of childbearing potential ...................................................................................................... 8 
4.3.1
 
Males ................................................................................................................................................. 9 
4.3.2
5 
SCREENING AND CONSENT ...................................................................................................................... 9 
5.1 
SCREENING ................................................................................................................................................ 9 
5.2 
INFORMED CONSENT ................................................................................................................................... 9 
 
Screening Investigations .................................................................................................................. 10 
5.2.1
 
Patient Screening Log ...................................................................................................................... 11 
5.2.2
6 
TRIAL ENTRY .......................................................................................................................................... 11 
6.1 
PATIENT REGISTRATION ............................................................................................................................. 11 
7 
TREATMENT DETAILS ............................................................................................................................. 12 
7.1 
DETAILS OF INVESTIGATIONAL MEDICINAL PRODUCT ....................................................................................... 12 
7.2 
INVESTIGATIONAL MEDICINAL PRODUCT SUPPLY............................................................................................. 12 
7.3 
PEMBROLIZUMAB ADMINISTRATION ............................................................................................................. 12 
7.4 
TREATMENT SCHEDULE .............................................................................................................................. 12 
7.5 
DOSE MODIFICATION AND TOXICITY MANAGEMENT........................................................................................ 15 
7.6 
SAMPLE COLLECTION ................................................................................................................................. 19 
 
Blood Collections ............................................................................................................................. 19 
7.6.1
 
Tissue Sample Collection ................................................................................................................. 19 
7.6.2
 
Stool Sample .................................................................................................................................... 19 
7.6.3
7.7 
QUALITY OF LIFE ASSESSMENT .................................................................................................................... 20 
7.8 
TREATMENT COMPLIANCE .......................................................................................................................... 20 
7.9 
CONCOMITANT MEDICATION ...................................................................................................................... 20 
 
Acceptable Concomitant Medications ............................................................................................. 20 
7.9.1
 
Prohibited Concomitant Medications .............................................................................................. 21 
7.9.2
7.10 
PATIENT FOLLOW UP ................................................................................................................................. 21 
7.11 
PATIENT WITHDRAWAL ............................................................................................................................. 22 
7.12 
EXPECTED TOXICITY, RESCUE MEDICATIONS AND SUPPORTIVE CARE ................................................................... 23 

 
 
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 Management of Infusion Reactions ................................................................................................ 23 
7.12.1
8 
TRANSLATIONAL RESEARCH ASSOCIATED WITH THE PEPS2 TRIAL ......................................................... 26 
9 
ADVERSE EVENT REPORTING ................................................................................................................. 26 
9.1 
REPORTING REQUIREMENTS ....................................................................................................................... 26 
 
Adverse Events ................................................................................................................................ 26 
9.1.1
 
Serious Adverse Events .................................................................................................................... 26 
9.1.2
 
Events of Clinical Interest ................................................................................................................ 26 
9.1.3
 
Reporting period .............................................................................................................................. 27 
9.1.4
9.2 
REPORTING PROCEDURE ............................................................................................................................ 27 
 
Site ................................................................................................................................................... 27 
9.2.1
 
PePS2 Trial Office ............................................................................................................................ 28 
9.2.2
 
Reporting to the Competent Authority and Research Ethics Committee ........................................ 29 
9.2.3
 
Investigators .................................................................................................................................... 29 
9.2.4
 
Trial Steering Committee ................................................................................................................. 29 
9.2.5
 
Manufacturer of Investigational Medicinal Product ....................................................................... 29 
9.2.6
10 
DATA HANDLING AND RECORD KEEPING ............................................................................................... 29 
10.1 
DATA COLLECTION .................................................................................................................................... 29 
 Case Report Form (CRF) ................................................................................................................... 29 
10.1.1
10.2 
ARCHIVING .............................................................................................................................................. 30 
11 
QUALITY MANAGEMENT ....................................................................................................................... 30 
11.1 
SITE SET-UP AND INITIATION ....................................................................................................................... 30 
11.2 
ON-SITE MONITORING .............................................................................................................................. 30 
11.3 
CENTRAL MONITORING ............................................................................................................................. 31 
11.4 
AUDIT AND INSPECTION ............................................................................................................................. 31 
11.5 
NOTIFICATION OF SERIOUS BREACHES .......................................................................................................... 31 
12 
END OF TRIAL DEFINITION ..................................................................................................................... 32 
13 
STATISTICAL CONSIDERATIONS .............................................................................................................. 32 
13.1 
DEFINITION AND CALCULATION OF OUTCOME MEASURES ................................................................................ 32 
 Primary Outcomes ........................................................................................................................... 32 
13.1.1
 Secondary Outcomes ....................................................................................................................... 32 
13.1.2
13.2 
METHODS OF ANALYSIS ............................................................................................................................. 33 
 Primary Outcomes ........................................................................................................................... 33 
13.2.1
 Secondary Outcomes ....................................................................................................................... 35 
13.2.2
14 
TRIAL ORGANISATIONAL STRUCTURE .................................................................................................... 36 
14.1 
SPONSOR ................................................................................................................................................ 36 
14.2 
COORDINATING CENTRE ............................................................................................................................. 36 
14.3 
TRIAL MANAGEMENT GROUP ..................................................................................................................... 36 
14.4 
TRIAL STEERING COMMITTEE ...................................................................................................................... 36 
14.5 
FINANCE ................................................................................................................................................. 36 
15 
ETHICAL CONSIDERATIONS .................................................................................................................... 37 
16 
CONFIDENTIALITY AND DATA PROTECTION ........................................................................................... 37 
17 
INSURANCE AND INDEMNITY................................................................................................................. 38 
18 
PUBLICATION POLICY ............................................................................................................................. 38 
19 
REFERENCE LIST ..................................................................................................................................... 39 
 
 

 
 
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APPENDICES ................................................................................................................................................... 41 
APPENDIX 1: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS CRITERIA  ................................................ 41 
APPENDIX 2: RECIST V1.1 CRITERIA ......................................................................................................................... 42 
APPENDIX 3: COCKCROFT AND GAULT EQUATION......................................................................................................... 45 
APPENDIX 4: CHARLSON INDEX ................................................................................................................................ 46 
APPENDIX 5: QUALITY OF LIFE QUESTIONNAIRES ......................................................................................................... 43 
APPENDIX 6: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE), VERSION 4.0 .......................................... 46 
APPENDIX 7: ADVERSE EVENT DEFINITION .................................................................................................................. 47 
APPENDIX 8: WMA DECLARATION OF HELSINKI .......................................................................................................... 50 
 
 
 

 
 
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LIST OF TABLES 
 
TABLE 1: SCHEDULE OF EVENTS ............................................................................................................................ X 
TABLE 2: ROUTINE LABORATORY TESTS .............................................................................................................. XV 
TABLE 3: DOSING INSTRUCTIONS FOR PEMBROLIZUMAB. ................................................................................. 12 
TABLE 4: DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-RELATED AES 
ASSOCIATED WITH PEMBROLIZUMAB ................................................................................................. 16 
TABLE 5: FREQUENCY OF SAMPLE COLLECTION ................................................................................................. 20 
TABLE 6: PEMBROLIZUMAB INFUSION REACTION DOSE MODIFICATION AND TREATMENT GUIDELINES ......... 24 
TABLE 7: A PATIENT’S PD-L1 CATEGORY IS INFERRED FROM THEIR PD-L1 PROPORTION SCORE ....................... 33 
TABLE 8: PEPS2 COHORTS AND CORRESPONDING VECTORS OF PREDICTIVE VALUES, X = (X1, X2, X3) ............... 34 
TABLE 9: PARAMETERS FOR NORMAL PRIOR DISTRIBUTIONS FOR THE ELEMENTS OF Θ .................................. 35 
 

 
 
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1 
BACKGROUND AND RATIONALE 
1.1 
Background 
 
Lung cancer is a devastating and very common healthcare problem. It is the most common 
cancer worldwide with 1.83 million new cases in 2012 (1). It is also the most common cause 
of cancer death worldwide with 1.69 million deaths in 2015 (2). In 2014 it was the most 
common cancer representing 13% of all cancers. There were 46, 400 new cases in the UK 
and the male to female ratio was almost equal at 12:10. Three quarter of cases are in people 
over the age of 65. Over the past 25 years the incidence has been steadily decreasing in 
Europe but in females has gone up by 70% in the same timeframe. The lifetime risk of 
developing lung cancer is 1 in 13 in men and 1 in 17 in women. The disease usually presents 
late with less than 25% having stage 1 or 2 disease. In the UK it accounts for 7% of all 
deaths. It is the most common cause of cancer death representing 22% of cancer death in 
2014, where 35,900 people died of the disease. Mortality in men has been decreasing over 
the past 25 years but in Europe has gone up by 63% and still continues to increase in 
women. 
 Pharmaceutical and Therapeutic Background 
1.1.1
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
Immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) which has been shown to negatively regulate antigen receptor 
signalling upon engagement of its ligands (PD-L1 and/or PD-L2) (3, 4). The structure of 
murine PD-1 has been resolved (5). PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type domain responsible for ligand binding and a 
cytoplasmic tail which is responsible for the binding of signalling molecules. The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signalling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signalling cascade (3, 6-8). 
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4 as both molecules regulate an overlapping set of signalling proteins (9, 
10). PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ 
and CD8+ T-cells, B-cells, T regs and Natural Killer (NK) cells (11, 12). Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells (13). 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 (9, 14-16). Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signalling motifs. Binding of PD-
L1 or PD-L2 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 antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to 
control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues (9). Although healthy organs express little (if 
any) PD-L1, a variety of cancers demonstrate abundant levels of this T-cell inhibitor. PD-L1 
expression in tumour tissues can be upregulated by oncogenic activation (innate immune 

 
 
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resistance – ALK or PTEN loss can increase PD-L1 expression). In adaptive immune 
resistance Interferon-gamma (IFN-γ) produced by infiltrating T lymphocytes upregulate PD-
L1 expression by tumour cells and thus act as a negative feedback mechanism to dampen 
an anti-tumour immune attack (17). 
 Pembrolizumab in Lung Cancer 
1.1.2
 
Pembrolizumab is a high affinity humanized IgG4 PD-1 blocking antibody antagonising the 
effects of both PD-L1 (IC50 0.1-0.3nM) and PD-L2 (0.5-0.9 nM). It lacks antibody-dependent 
cell-mediated cytotoxicity (ADCC) and Complement-dependent cytotoxicity (CDC) activity 
and thus has no cytotoxic effect on PD-1 expressing T cells (18). In the PePS2 trial both 
untreated and previously treated patients will be eligible for treatment with MK-3475. Data on 
495 patients with NSCLC treated with pembrolizumab have been published (19). Four 
hundred and ninety five patients were treated, 101 of these receiving pembrolizumab as first 
line therapy. Treatment was well tolerated with grade 3 or higher adverse events (AEs) being 
reported in 9.5%. Grade 3 or greater pneumonitis was reported in 1.8% with a death in 1 
patient. The commonest immune-mediated AE was hypothyroidism (all grades 6.9%) easily 
managed with replacement therapy. Grade 3 or greater rash, transaminitis and diarrhoea 
was seen in only 0.2%, 0.6% and 0.6% respectively: all grade infusion reactions were 3% 
with only 1 patient having a severe infusion reaction. The overall response rate was 19.4%, 
24.8% in first line patients and 18% in those who had received previous therapy. Stable 
disease rate was 21.8%. Median duration of response was 12.5 months, 23.3 months in 
those receiving pembrolizumab first line. There was no difference in response duration 
according to proportion of tumour cells expressing PD-L1 (proportion score). Of these, 23.2% 
of patients had a proportion score of at least 50%, 37.6% with a score 1 - 49% and 39.2% 
with a score <1%. The response rate in these 3 subsets was 45.2%, 16.5% and 10.7% 
respectively. Median survival and progression free survival curves were very similar for those 
with proportion scores of <1% or 1-49% and survival was less in these two groups compared 
with patients with proportion score >50%.  
Subsequent randomised trials have demonstrated superior overall survival for patients who 
had received previous platinum-based chemotherapy, with PD-L1 expression >1% receiving 
pembrolizumab with the second line standard of care comparator docetaxel and improved 
survival when delivered as a first line agent compared to platinum chemotherapy in patients 
with >50% than cell PD-L1 expression (20-21). Thus, pembrolizumab has high-level activity 
in NSCLC with long durability of response in both first and subsequent line patients.  
 
1.2 
Trial Rationale 
 Rationale for Patient Population 
1.2.1
 
Many patients with lung cancer have impaired performance status making them ineligible for 
trials of new therapies including anti PD-1: all of the trials reported thus far have been in 
patients with performance status (PS) 0-1. In the National Lung Cancer Audit Database, 
18.2% of the PS2 patients had adenocarcinoma and 21.5% had squamous cell cancer 
(personal communication). In a large Polish series, 30.8% of patients were PS2 and the 
percentages for males and females were almost identical (22). 
 
Clinical trials of standard-of-care therapy have been successfully performed in the PS2 only 
population. Overall survival and progression free survival was significantly better for PS2 
patients treated with paclitaxel/carboplatin compared to erlotinib with median overall survival 
(mOS) of 9.7 months for chemotherapy patients. These patients had a 37% Grade 3/4 rate of 
adverse events (AEs) and there was a 6% rate of treatment-related death (23). In a separate 
PS2 
only 
clinical 
trial, 
PS2 
patients 
had 
significantly 
better 
survival 
with 

 
 
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pemetrexed/carboplatin compared with pemetrexed alone: again PS2 patients treated with 
doublet chemotherapy had median survivals of around 9 months (24). There was a 3.9% 
treatment-related death rate in the combination chemotherapy arm. These results show that 
chemotherapy can be delivered to PS2 patients but that the outcomes are modest and 
toxicity not insignificant. Importantly, they demonstrate the feasibility of performing clinical 
trials in this population. 
 
Importantly for this trial, there is no reason why the good clinical tolerability or durable 
response rates for pembrolizumab should differ for PS2 patients when compared to their 
PS0-1 counterparts. This trial prospectively evaluates the clinical hypothesis with rigorous 
ascription of PS2 status. 
 
 Rationale for Design 
1.2.2
 
This is an open label, multi-centre, single arm phase II trial registering 60 patients with 
NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 2. 
Patients are eligible for the trial irrespective of line of treatment and the design accounts for 
PD-L1 tumour status in order to assess the implication of treatment outcome according to 
PD-L1 status in this population and to ascertain accurate data on PD-L1 status in these 
patients. 
 
The primary objectives are to characterise the safety profile and tolerability of pembrolizumab 
and to define durable clinical benefit (complete response (CR), partial response (PR) or 
stable disease (SD) ≥18 weeks). 
 
The excellent therapeutic index of pembrolizumab makes its testing in PS2 NSCLC highly 
attractive. Essential to the success of this programme is the highly accurate ascription of PS 
in each patient entered. In particular, it is crucial that Investigators do not downgrade a 
patient who is truly PS1 to PS2 in order to offer them the trial. The question then becomes 
who is best placed to assess PS – physician or patient? Is a patient assessment less prone 
to manipulation in order to satisfy eligibility criteria? There are a number of publications 
pertinent to this. Dajczman and colleagues used a PS assessment tool designed for patient 
use derived from Box 4 of the validated patient-generated subjective global assessment 
scale and analysed congruency with physician assessed PS (MD-PS) on the ECOG scale 
(25). Patient-PS was not congruent with MD-PS in 54% of cases with 69% of the patients in 
this group rating themselves of poorer PS than the physician. Importantly, physicians 
seemed more accurate in distinguishing PS1 and PS2 – median survival of patient assessed 
PS1 and PS2 patients was virtually identical but there was a clear difference in survival for 
PS1 and PS2 patients assessed as such by the physician. Patients and physicians assessed 
whether they were eligible for a clinical trial requiring PS0/1. In 24/30 cases where there was 
disagreement on trial entry, the patient would have excluded themselves. However, these 24 
patients had a median survival of 8.7 months numerically higher than the entire patient 
assessed PS1 cohort. These data strongly suggests that physicians are more discriminating 
in their ascription of PS. These data are very similar to those of Ando et al. who showed in 
univariate and multivariate analysis that assessment of PS 0, 1 and 2 by physicians 
successfully stratified survival whereas the patients failed to distinguish PS1 and PS2 
survival (26). The Cox model including oncologist assessed PS best fitted the actual survival 
data. There was no significant difference in the assessment of nurses and oncologists. Thus, 
oncologist assessed PS appears to be most accurate and discriminatory and will be used 
here. Exact criteria for ascription of PS2 status will be recorded and checked at the PePS2 
Trial Office as appropriately eligible. Patient-assessed PS will be recorded and correlations 
will be made between patient and physician PS. 
 

 
 
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 Rationale for Choice of Treatment 
1.2.3
 
Rationale for dose: 
A population pharmacokinetic (PK) analysis has been performed using serum concentration 
time data from 476 patients. The population PK evaluation revealed that there was no 
significant impact of tumour burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. The differences in exposure for a 200 mg 
fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for pembrolizumab, 
therefore a 200 mg flat dose has been selected. 
 
Rationale for Q3W dosing schedule: 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to Summary of Product 
Characteristics - SPC). Pharmacodynamic data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days). 
 
2 
OBJECTIVES AND OUTCOME MEASURES 
2.1 
Objectives 
 Primary Objectives 
2.1.1
 
The first primary objective of this trial is to determine that pembrolizumab is safe and 
tolerable at the selected dose of 200 mg 3 weekly, in NSCLC patients with a physician 
scored ECOG PS of 2. 
 
The second primary objective is to allow detection of durable clinical benefit to justify further 
investigation in subsequent studies. 
 Secondary Objectives 
2.1.2
 
• Quality of life will be assessed using the FACT-L questionnaire and EQ-5D 
questionnaire 
• All patients will be comprehensively assessed by the Charlson’s co-morbidity score and 
the outcome analysed by the severity of any associated co-morbidities 
• Progression free survival time, time to progression and overall survival time. 
 Exploratory Objectives 
2.1.3
 
To discover possible biomarkers for the prediction of a response to treatment with 
pembrolizumab. 
 
2.2 
Outcome Measures 
 
The trial includes two co-primary outcome measures of toxicity and efficacy (as defined 
below) and a set of secondary outcome measures (listed below). 

 
 
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 Primary Outcome Measures 
2.2.1
2.2.1.1 Toxicity 
 
AEs will be recorded in relation to each cycle of treatment and graded according to Common 
Terminology Criteria for Adverse Events (CTCAE) criteria (see Appendix 6). The toxicity co-
primary outcome measure for the trial is defined as the occurrence of a treatment-related 
dose delay or treatment discontinuation due to an adverse event. 
2.2.1.2 Efficacy 
 
Patients will have Computerised Tomography (CT) scans every 9 weeks from baseline until 
disease progression. On each occasion, overall tumour burden will be assessed using 
RECIST version 1.1 (see Appendix 2). The efficacy co-primary outcome measure for the trial 
is durable clinical benefit defined as the occurrence of  
a complete response (CR), partial response (PR) or stable disease (SD) without prior 
progressive disease (PD) at or after the second scheduled CT scan (scheduled to occur at18 
weeks). 
 
  Secondary Outcome Measures 
2.2.2
2.2.2.1 Objective Response 
 
Patients will have CT scans every 9 weeks from baseline until disease progression. On each 
occasion, overall tumour burden will be assessed using RECIST version 1.1 (see Appendix 
2). Best overall response is the best response recorded over the whole period of assessment 
and could be CR, PR, SD, progressive disease (PD) or inevaluable for response (for which 
reasons such as early death due to disease or early death due to toxicity will be specified). 
Objective response (OR) is the occurrence of CR or PR as the best overall response. OR will 
be based on responses confirmed using the subsequent 9-weekly scan but OR based on 
unconfirmed responses will also be reported. 
2.2.2.2 Health Related Quality of Life 
 
This is defined as the functional effect of a medical condition and/or its consequent treatment 
upon a patient. The purpose of Health related quality of life (HRQoL) measurement is to 
quantify the degree to which the medical condition or its treatment impacts the individual’s 
life in a valid and reproducible way. HRQoL will be assessed over time using FACT-L 
questionnaire and EQ-5D questionnaire (see Appendix 5). 
 
2.2.2.3 Time to Progression 
 
This is defined as the time from commencement of trial treatment to the date of CT scan 
when progressive disease is first recorded. Patients with no recorded progression at the time 
of analysis or who die without recorded progression will be censored at the date of the CT 
scan when they were last recorded with an evaluable measure that was not progression.  
2.2.2.4 Progression-Free Survival Time 
 
This is defined as the time from commencement of trial treatment to the date of CT scan 
when progressive disease first recorded or date of death without previously recorded 
progression. Patients who are alive with no recorded progression at the time of analysis will 

 
 
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be censored at the date of the CT scan when they were last recorded with an evaluable 
measure that was not progression. 
2.2.2.5 Overall Survival Time 
 
This is defined as the time from commencement of trial treatment to the date of death. 
Patients who are alive at the time of analysis will be censored at the date last seen alive. 
2.2.2.6 Duration of Objective Response and Duration of Stable Disease 
 
Duration of objective response and duration of stable disease are defined as the time from 
commencement of trial treatment to the date of the subsequent CT scan when progressive 
disease is first confirmed or date of death without previously recorded progression. This 
outcome is calculated and reported separately for patients who achieve an OR or SD. 
Patients experiencing OR or SD who are alive with no recorded progression at the time of 
analysis will be censored at the date of the CT scan when they were last recorded with an 
evaluable measure that was not progression. 
 
3 
TRIAL DESIGN 
 
The trial is a multi-centre single-arm phase II trial, testing pembrolizumab in a population of 
Eastern Cooperative Group (ECOG) performance status 2 patients with non-small cell lung 
cancer. It has co-primary outcome measures of toxicity and efficacy (as defined in Section 
2.2.1). The trial will be an all-comers design and PD-L1 expression will be measured and 
included as an integral part of the trial design as a potentially predictive biomarker for 
response. In addition, whether or not patients are pre-treated will also be considered as a 
potentially predictive factor. We have used a bespoke design based on a Bayesian bivariate 
model (Brock et al.; to be submitted) and the target total recruitment is 60 evaluable patients. 
The trial will be a single stage design but will include interim monitoring of toxicity to ensure 
safety. The definition of an evaluable patient is given in Section 7.11. Details on the statistical 
basis behind this design are given in Section 13. 
 
4 
ELIGIBILITY 
4.1 Inclusion Criteria 
 
• Patients must have completed all standard of care therapy that the treating oncologist 
deems appropriate. All lines of therapy will be allowed. 
• Histologically confirmed NSCLC and, if possible, confirmed PD-L1 status. Patients with 
both PD-L1 positive and negative tumours are eligible. Patients who have had systemic 
therapy since the biopsy do not need to have a repeat biopsy. 
o If the PD-L1 status has already been obtained from a nationally recognised and 
MSD-approved laboratory, this will be acceptable and repeat PD-L1 staining will not 
be required. 
o If a patient has had a repeat biopsy for the sole purpose of PD-L1 staining for the 
PePS2 trial but the biopsy failed to yield sufficient cells for PD-L1 status, this patient 
will still be eligible to enter the PePS2 trial but will be categorised as PD-L1 non-
evaluable. 

 
 
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• Patients must have a performance status of 2 on the ECOG Performance scale 
(Appendix 1) with no deterioration over the previous 2 weeks assessed by consenting 
physician. 
o Patients must be ambulatory and capable of all self-care but unable to carry out any 
work activities. 
o Patients must be up and about more than 50% of waking hours. 
• Life expectancy >12 weeks. 
• CT scan of chest and abdomen within 28 days of starting pembrolizumab demonstrating 
uni-dimensionally measurable disease as per RECIST version 1.1 (Appendix 2). 
• Demonstrate adequate haematological function: 
o Platelet count ≥100 x 109 /L 
o Neutrophils ≥1.5 x 109/L 
o Haemoglobin ≥ 90 g/L 
• Demonstrate adequate hepatic function: 
o Serum bilirubin ≤1.5 x upper limit of normal (ULN) 
o Serum transaminases ≤2.5 x ULN 
• Demonstrate adequate renal function 
o Creatinine clearance <1.5 times ULN concurrent with creatinine clearance >50 
ml/min (calculated by Cockcroft and Gault equation – see Appendix 3). If this is ≤ 50 
ml/min then an isotopic Glomerular Filtration Rate (GFR) may be carried out and 
must be > 50 ml/min 
• Age ≥ 18 years. 
• Provision of signed and dated, written informed consent prior to any trial specific 
procedures, sampling and analyses. 
• Patients must agree to the use of contraception as detailed in section 4.3. 
 
4.2 
Exclusion Criteria 
 
• Patients who do not meet the criteria of performance status = 2 on the ECOG 
Performance scale (Appendix 1) i.e. patients should not be ambulatory and able to carry 
out work of a light or sedentary nature e.g. light house work, office work. 
• Untreated symptomatic brain or leptomeningeal metastatic disease. 
• Medical or psychiatric conditions compromising informed consent. 
• Any medical condition which in the opinion of the Investigator would compromise the 
ability of the patient to participate in the trial or which would jeopardise compliance with 
the protocol. 
• Patient who has had chemotherapy, radioactive or biological cancer therapy within 4 
weeks prior to the first dose of trial therapy, or who has not recovered to CTCAE grade 1 
or better from the Adverse Event (AE) due to cancer therapeutics administered more 
than 4 weeks earlier. Patient who has had erlotinib, gefitinib, afatinib, or crizotinib within 
1 week prior to the first dose of trial therapy, or who has not recovered to CTCAE Grade 
1 or better from the AE due to any of these drugs administered more than 1 week earlier. 
Patient who has had ipilimumab therapy may be enrolled if requirements specified in 
Inclusion Criterion are met. 
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
• 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. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
• Patient has risk factors for bowel obstruction or bowel perforation (examples include but 
not limited to a history of acute diverticulitis, intra-abdominal abscess and abdominal 
carcinomatosis). 
• Patient has a known history of malignancy, unless the patient has undergone potentially 
curative therapy with no evidence of that disease for 3 years. 
• Has a history of non-infectious pneumonitis requiring steroids or has active pneumonitis 
or significantly reduced transfer coefficient (KCO). 
• Female patients of child bearing potential should be using adequate contraceptive 
measures, should not be breast feeding and must have a negative pregnancy test prior 
to start of dosing. 
• Patient previously had a severe hypersensitivity reaction to treatment with another 
monoclonal antibody. 
• Patient had prior treatment targeting PD-1: PD-L1 axis. 
• Patient is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active 
Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected); patients 
with negative Hepatitis C antibody testing may not need RNA testing. 
• Known history of tuberculosis. 
• Patient has an active infection requiring therapy. 
• Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
• Patient is, at the time of signing informed consent, a regular user (including “recreational 
use”) of any illicit drugs or had a recent history (within the last year) of substance abuse 
(including alcohol). 
• Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable 
following treatment for these conditions (including therapeutic thoraco- or paracentesis) 
is eligible. 
• Any of the following cardiac criteria: 
o Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive 
ECGs 
o Any clinically important abnormalities in rhythm, conduction or morphology of resting 
ECG e.g., complete left bundle branch block, third degree heart block 
o Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years of age or any 
concomitant medication known to prolong the QT interval. 
 
4.3 
Contraception 
 Women of childbearing potential 
4.3.1
 
Women of childbearing potential are defined as women who have not had a hysterectomy 
and oophorectomy. Women with amenorrhea for <2 years will only be considered not to be of 
reproductive potential if they have a documented Follicle-Stimulating Hormone (FSH) value 
in the postmenopausal range. 
 
Adequate contraception should be used from the time of screening, during the trial and for at 
least 90 days after completion of treatment. 
 
Acceptable methods of contraception include total abstinence (if this is the patient’s usual 
and preferred lifestyle choice), tubal ligation, combined oral, transdermal or intra-vaginal 
hormonal contraceptives, medroxyprogesterone injections (e.g. Depo-provera), copper-

 
 
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PePS2 version 6.0_10-Jul-2018 
 
banded intra-uterine devices, hormone impregnated intra-uterine systems and vasectomised 
partners. All methods of contraception (with the exception of total abstinence) should be 
used in combination with the use of a condom by their male sexual partner for intercourse. 
 
 Males 
4.3.2
Male patients with sexual partners who are pregnant or who could become pregnant (i.e. 
women of child-bearing potential) should use a condom during sexual intercourse during the 
trial and for at least 90 days after completion of treatment. 
 
5 
SCREENING AND CONSENT 
5.1 Screening 
 
Patients attending oncology clinic with a diagnosis of NSCLC and a PS2, and who in the 
Investigator’s opinion would be potentially suitable for clinical trial entry will be screened for 
entry onto the trial. If informed consent is given, PD-L1 expression will be measured from 
either an archived biopsy if available, or a newly obtained biopsy. A repeat biopsy will not be 
required if the PD-L1 status has already been obtained from a nationally recognised and 
MSD-approved laboratory. Sites must send an anonymised copy of Pathology report to 
confirm PD-L1 testing during screening to the PePS2 Trial Office, before the patient can be 
registered. 
The Investigator will also conduct a full screening evaluation to ensure that the patient 
satisfies all inclusion and exclusion criteria. Investigators must keep a pre-screening log of all 
patients who receive a Patient Information Sheet, a screening log of all patients who consent 
to the trial and a pre-registration screening log of all patients who have tumour tissue sent for 
PD-L1 testing for the PePS2 trial.  
Patients’ whose PD-L1 status was determined prior to the PePS2 trial will still need a 
screening number from the Pre-Registration Screening Log and will also need to complete 
the Pre-Registration Screening Form and enter date PD-L1 results obtained. Regular 
recruitment updates will be circulated to site staff. 
 
5.2 
Informed Consent 
 
It is the responsibility of the Investigator or delegate specified on the Site Signature and 
Delegation Log to obtain written informed consent for each patient prior to performing any 
trial related procedure. Specific Patient Information Sheets are provided to facilitate this 
process. Investigators must ensure that they adequately explain the aim, trial treatment, 
anticipated benefits and potential hazards of taking part in the trial to the patient. The 
Investigator should also stress that the patient is completely free to refuse to take part or 
withdraw from the trial at any time. The patient should be given ample time to read the 
Patient Information Sheet and to discuss their participation with others outside of the site 
research team. The patient must be given an opportunity to ask questions which should be 
answered to their satisfaction. The right of the patient to refuse to participate in the trial 
without giving a reason must be respected. 
 
If the patient expresses an interest in participating in the trial they should be asked to sign 
and date the latest version of the Informed Consent Form. The Investigator or delegate must 
then sign and date the form. A copy of the Informed Consent Form should be given to the 
patient, a copy should be filed in the hospital notes, and the original placed in the Investigator 
Site File (ISF). Informed consent should be obtained within 28 days of starting treatment; 
otherwise it will be necessary to re-consent the patient. Once the patient is entered into the 

 
 
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trial the patient’s Trial Number (TNO) should be entered on the Informed Consent Form 
maintained in the ISF. In addition, if the patient has given explicit consent by signing the copy 
of the Informed Consent Form a copy of the signed Informed Consent Form must be sent in 
the post to the PePS2 Trial Office for review. Details of the informed consent discussions 
should be recorded in the patient’s medical notes, this should include date of, and 
information regarding, the initial discussion, the date consent was given, with the name of the 
trial and the version number of the Patient Information Sheet and Informed Consent Form. 
Throughout the trial the patient should have the opportunity to ask questions about the trial 
and any new information that may be relevant to the patient’s continued participation should 
be shared with them in a timely manner. On occasion it may be necessary to re-consent the 
patient, in which case the process above should be followed and the patient’s right to 
withdraw from the trial respected. 
 
Electronic copies of the Patient Information Sheet and Informed Consent Form are available 
from the PePS2 Trial Office and should be printed or photocopied onto the headed paper of 
the local institution. 
 
Details of all patients approached about the trial should be recorded on the Patient 
Screening/Enrolment Log and with the patient’s prior consent their General Practitioner (GP) 
should also be informed that they are taking part in the trial. A GP Letter is provided 
electronically for this purpose. 
 
 Screening Investigations 
5.2.1
5.2.1.1 Histologically Confirmed PD-L1 status 
 
As part of the pre-screening registration process, PD-L1 testing may be carried out on an 
archival biopsy sample if available or a newly obtained biopsy, at a nationally recognised 
MSD-approved laboratory for PD-L1 staining. Repeat biopsies are not required if the PD-L1 
status is already known (see section 5.1). 
 
Biopsies taken for PePS2 may be obtained by Endobronchial ultrasound (EBUS) or 
Computer-Tomography (CT)-guided. Five slides fresh cut sections from Formaldehyde Fixed 
Paraffin Embedded (FFPE) tissue will be assessed by the site Pathologist for PD-L1 testing 
with >50% tumour content and at least 50 viable neoplastic cells overall. These slides will 
then be shipped to an MSD-approved laboratory for PD-L1 testing and the Trial Office will 
inform sites of successful staining. The PD-L1 status of the patient must be known for patient 
to be eligible for the trial. The only exception to this will be patients who have submitted to a 
repeat biopsy for the explicit purpose of ascertaining the PD-L1 status in the PePS2 trial and 
where PD-L1 staining has failed on that repeat biopsy. 
5.2.1.2 Screening Assessments 
 
Please see Table 1 Schedule of Assessments, Table 2 Routine Laboratory Tests and the 
Treatment Assessments flowchart for detailed description of the procedures and tests. 
After written informed consent is obtained, the following screening procedures must take 
place:- 
Up to 28 days prior to trial treatment: 
• Medical history – Radiographic studies performed prior to study trial entry may be 
collected for review by the Investigator. 
• Prior Medications 
• ECOG assessment 

 
 
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• Coagulation parameters 
• CT scan with contrast (RECIST v1.1 reporting – Appendix 2) 
• ECG 
• HIV, Hepatitis B and C testing 
• Tumour biopsy if archived tissue is not available 
Up to 7 days prior to trial treatment 
• Physical exam 
• Charlson Index 
• Vital signs 
• Concomitant medications 
• ECOG assessment 
• Haematology 
• Urinalysis 
• Clinical chemistry 
• Renal function - GFR 
• Thyroid function and cortisol 
 
Within 72 hours of first dose of pembrolizumab 
• Pregnancy test if applicable 
 Patient Screening Log 
5.2.2
 
The following details of all patients screened for participation in this trial will be collected: 
• Screening number 
• Date screened 
• Date of Birth 
• Sex 
• Whether the patient was eligible and reasons for ineligibility 
• Whether the patient gave written informed consent 
• Whether the person was registered 
• Reasons(s) patient was not registered 
 
6 
TRIAL ENTRY 
 
Prior to recruitment of patients into the trial, the Principal Investigator for each site, or their 
delegate, should have returned all required documentation to the PePS2 Trial Office, and the 
site personnel involved with the trial must have received appropriate training from the Trial 
Coordinator. 
 
6.1 Patient Registration 
 
Patients must be registered with the PePS2 Trial Office at Cancer Research UK Clinical 
Trials Unit (CRCTU) at the University of Birmingham. 
• Prior to trial entry, sites should complete the first page of the Pre-Registration Screening 
Form and phone the Trial Office to 
o give the site-specific screening number from the pre-registration screening log 
o confirm and email an anonymised pathology report with PD-L1 results from an 
archived tissue or 
o confirm that slides from a newly obtained biopsy will be sent with the Pre-
Registration Screening Form to an MSD-approved laboratory for PD-L1 staining. 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
• After all eligibility criteria have been met, participating sites must fax copies of the 
Eligibility Forms to the PePS2 Trial Office and the patient’s eligibility will be confirmed at 
registration. 
• Sites must then telephone the registration line with the details required on the 
Registration Form and the patient will be registered over the phone and allocated a Trial 
Number (TNO). The registration line will be open during office hours, 9am-5pm, Monday-
Friday. 
• A fax will be sent to the main site administrator and Pharmacy confirming the details of 
registration. Trial drug prescriptions must include the patient’s TNO and dose. 
• Sites should post a copy of the Informed Consent Form to the PePS2 Trial Office. 
7 
TREATMENT DETAILS 
7.1 
Details of Investigational Medicinal Product 
 
Pembrolizumab is an Investigational Medicinal Product (IMP) for the purposes of this trial. 
Full details of the IMP are contained in the PePS2 Pharmacy Manual, which also lists the 
Pharmacist’s responsibilities, details of labelling, record keeping for prescribing, dispensing, 
and accountability of the IMP. The PePS2 Pharmacy Manual will be sent to the responsible 
Pharmacist. 
7.2 
Investigational Medicinal Product Supply 
 
Pembrolizumab will be supplied, packaged and delivered to sites by Almac. See the PePS2 
Pharmacy Manual for further information. 
7.3 Pembrolizumab Administration 
 
Pembrolizumab will be administered as a 30 minute IV infusion, with a window of -5 and +10 
minutes, at a flat dose of 200 mg. A dosing interval every 3 weeks (Q3W) will be employed. 
See the PePS2 Pharmacy Manual for further information about pembrolizumab. 
Table 3: Dosing Instructions for pembrolizumab. 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
flat dose 
Q3W 
30 minute IV 
infusion 
For 2 years or 
until progression 
Experimental 
7.4 
Treatment Schedule 
 
For details please refer to the Table 1: Schedule of Events (see page x) and the Treatment 
Assessments Schedule (see page 14). 
 
0121 414 6788 (Tel) 
0121 414 3529 (Fax) 
Or 
PePS2@trials.bham.ac.uk 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Patients will be administered pembrolizumab for up to 2 years or until progression; each 
cycle being 21 days. Trial treatment should be administered on day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Schema. Trial 
treatment may be administered up to 3 days before or after the scheduled day 1 of each 
cycle due to administrative reasons. Trial treatments will be administered on an outpatient 
basis. 
Patients with unacceptable toxic side effects from pembrolizumab will come off treatment 
until disease progression. 
 
In the case of CR it is at the discretion of the Investigator to keep a patient on trial treatment 
or to discontinue trial treatment based on the following guidelines. This decision will be based 
on the clinical judgment of a patient's overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Patients who have a confirmed complete response 
by two scans ≥4 weeks apart and who have been on pembrolizumab treatment for at least 6 
months may discontinue pembrolizumab treatment at the discretion of the Investigator after 
receiving at least two doses beyond the initial determination of CR. Pembrolizumab may be 
resumed upon disease recurrence in these patients. 
 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment 
o 
Vital signs/Weight/Physical exam 
o 
ECOG PS 
o 
FBC/serum chem. panel 
o 
Tumour imaging/tumour biopsy 
o 
ECG & urinalysis 
o 
Thyroid/cortisol 
o 
Demographics/Medical History/Prior 
Medications 
o 
HIV/Hep B & C 
o 
Pregnancy Test 
o 
GFR/coagulation 
o 
Charlson Index 
Cycle 3 (± 3 days) 
o 
Vital signs/Weight/Physical 
exam 
o 
ECOG PS/HRQoL 
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
10 ml blood for PBMC 
Cycle 10 (± 3 days) 
o 
Vital signs/Weight/Physical exam 
o 
ECOG PS/HRQoL 
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
Urinalysis/ Tumour imaging 
o 
Thyroid/cortisol/10 ml blood for 
PBMC 
o 
Plasma 
cytokine/chemokine/proteomics 
o 
ctDNA 
Cycle 1/Day 1 
o Vital signs/Weight 
o ECOG PS/HRQoL 
o AEs/Conmed. review 
o FBC/serum chem. panel 
o 60 ml blood for PBMC 
o Plasma for cytokine/chemokine & 
proteomics 
o Germline DNA/ctDNA 
o Stool sample 
Cycle 2 (± 3 days) 
o 
Vital signs/Weight/Physical exam 
o 
ECOG 
 
PS/HRQoL
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
Thyroid/cortisol/60 ml blood for PBMC 
Cycle 4 (± 3 days) 
o 
Vital signs/Weight/Physical exam 
o 
ECOG PS/HRQoL 
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
AEs/Conmed. review 
o 
Tumour imaging/Urinalysis 
o 
Thyroid/cortisol/60 ml blood for  
PBMC 
o 
Plasma 
cytokine/chemokine/proteomics 
o 
ctDNA 
Cycle 5 (± 3 days) 
o 
Vital signs/Weight/Phys. 
exam 
o 
ECOG PS/HRQoL 
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
AEs/Conmed. review 
o 
10 ml blood for PBMC 
Cycle 7 (± 3 days) 
o 
Vital signs/Weight/Physical exam 
o 
ECOG PS/HRQoL 
o 
AEs/Conmed. review 
o 
FBC/serum chem. panel 
o 
Tumour imaging 
o 
10 ml blood for PBMC 
o 
Plasma 
cytokine/chemokine/proteomics 
o 
ctDNA 
Cycle 8 (± 3 days) 
o
Vital signs/Weight/Phys. 
exam 
o
ECOG PS/HRQoL 
o
AEs/Conmed. review 
o
FBC/serum chem. panel 
o
Thyroid/cortisol 
Cycle 9 (± 3 days) 
o Vital signs/Weight/Physic. 
exam 
o ECOG PS/HRQoL 
o AEs/Conmed. review 
o FBC/serum chem. panel 
o AEs/Conmed. review 
Cycle 6 (± 3 days) 
o
Vital signs/Weight/Phys. 
exam 
o
ECOG PS/HRQoL 
o
AEs/Conmed. review 
o
FBC/serum chem. panel 
o
AEs/Conmed. review 
o
Thyroid/cortisol 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
7.5 
Dose Modification and Toxicity Management 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
Immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 4. 
 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Table 4: Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv4.0) 
Action taken to 
pembrolizumab 
AE management with 
corticosteroid1, 4 and/or other 
therapies 
Monitoring and Supportive Care 
Pneumonitis 
Grade 2 
Withhold2, 3  
• Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper 
• Monitor subjects for signs and symptoms 
of pneumonitis 
• Evaluate subjects with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
• Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or recurrent 
Grade 2 
Permanently discontinue 
Diarrhoea / Colitis 
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper 
• Monitor subjects for signs and symptoms 
of enterocolitis (i.e. diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(i.e. peritoneal signs and ileus). 
• Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
• Subjects with diarrhea/colitis 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. 
Grade 4 or recurrent Grade 3 
Permanently discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1mg/kg prednisone 
or equivalent) followed by taper 
• Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently discontinue 
• Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv4.0) 
Action taken to 
pembrolizumab 
AE management with 
corticosteroid1, 4 and/or other 
therapies 
Monitoring and Supportive Care 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset T1DM or  
Grade 3 or 4 hyperglycemia 
associated with evidence of 
β-cell failure 
Withhold 
• Initiate insulin replacement 
therapy for subjects with T1DM 
• Administer anti-hyperglycemic in 
subjects with hyperglycemia 
• Monitor subjects for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids to 
treat secondary adrenal 
insufficiency and initiate 
hormonal replacements as 
clinically indicated. 
• Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold until improved to 
Grade <2 and if controlled 
with hormone 
replacement. Otherwise 
permanently discontinue 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-selective beta-
blockers (e.g. propranolol) or 
thionamides as appropriate 
• Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold  until recovery to 
Grade ≤1. Otherwise 
permanently discontinue 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyroinine) per standard of 
care 
• Monitor for signs and symptoms of 
thyroid disorders. 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by taper. 
• Monitor for changes of renal function 
Grade 3 or 4 
Permanently discontinue 
Skin Reactions 
Grade 3 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Monitor for suspected severe skin 
reactions. 
Grade 4 
Permanently discontinue 
Stevens-Johnson 
syndrome (SJS) 
Suspected SJS or TEN 
Withhold 
• Refer to a specialist unit for 
assessment and treatment. 
• Monitor for suspected servre skin 
reactions. 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Immune-related 
AEs 
Toxicity grade or 
conditions (CTCAEv4.0) 
Action taken to 
pembrolizumab 
AE management with 
corticosteroid1, 4 and/or other 
therapies 
Monitoring and Supportive Care 
or toxic epidermal 
necrolysis (TEN) 
suspected 
Confirmed SJS or TEN 
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently discontinue 
All Other 
immune-related 
AEs 
Intolerable/  
persistent Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Grade 3 
Withhold or discontinue 
based on the type of 
event5 
Grade 4 or recurrent Grade 3 
Permanently discontinue 
Footnotes: General Instructions for management of irAE 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. For subjects with Grade 3 or 
4 immune-related endocrinopathy, pembrolizumab may be resumed when AE improves to Grade 2 or lower and is controlled with hormonal replacement therapy. 
3. For situation where pemborlizumab is withheld initially, pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced 
to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
4. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
5. Events that require discontinuation include and not limited to:  Gullain-Barre Syndrome, encephalitis 
Note: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled 
with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 

 
 
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PePS2 version 6.0_10-Jul-2018 
 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
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 
recommence trial therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the PePS2 Trial Office. The reason for interruption should be documented in 
the patient's medical notes and on the CRF. 
 
7.6 
Sample Collection 
 Blood Collections 
7.6.1
 
Blood collection for safety evaluation assumes priority over other procedures. Whenever 
possible, pre-treatment blood samples should be obtained by fresh peripheral venepuncture. 
If a patient does not have peripheral access, the sample may be collected from a central 
catheter immediately after an initial withdrawal of at least 10 ml of blood; or preferably, after a 
series of other blood sample collections from the central catheter. 
 
For details on sample collection and processings, please refer to the PePS2 Laboratory 
Manual. 
 Tissue Sample Collection 
7.6.2
 
Where patients have given consent, a pre-registration, pre-treatment baseline biopsy will be 
taken for PD-L1 assessment. In addition, an optional end of treatment biopsy may be taken if 
patients have responded on treatment for 18 weeks but have now relapsed (maximum one 
per patient). Specific instructions for tissue collection and shipment are provided in the 
PePS2 Laboratory Manual. 
 Stool Sample 
7.6.3
 
A stool sample will be obtainedonce onlyat any time post-registration, pre-treatment and 
before the start of the first infusion. A stool sample, no less than 20g, should be collected by 
the patient at home, frozen and stored in a stool sample container. The stool sample should 
be frozen at the point of collection. 
 
Sites will be provided with stool sample containers, sample bags, silver freezer sheets and 
padded envelopes and should provide patients with the instructions and materials to freeze 
stool samples as follows: 
a. 
In preparation for the collection of stool sample, soak the silver freezer sheet in fresh 
warm water for 10 mins. 
b. 
Place the freezer sheet in freezer at home for at least 3 hours. 
c. 
After collection of stool in stool sample container, place container in sample bag and 
wrap around in frozen freezer sheet. 
d. 
Place the stool sample, bag and freezer pack in the padded envelope, seal and put in 
freezer. 
e. 
At next hospital visit, take the padded envelope containing stool sample and hand to 
PePS2 Research Team. 
 
Stool samples will remain frozen for up to 3h if left in padded envelope with freezer pack. 
The stool sample should be immediately transferred to a -80°C freezer in the pre-labelled 
Stool Only freezer box. Specific instructions for labelling and shipment are detailed in the 
PePS2 Laboratory Manual. 

 
 
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Table 5: Frequency of sample collection 
Time-point 
Tumour 
biopsy 
PBMC 
sample 
(60 ml) 
Stool 
sample 
Cytokine/ 
Chemokine 
Panel & 
Proteomics 
(plasma) 
Germline 
DNA 
(whole 
blood) 
ctDNA 
 (plasma) 
Post-registration, 
pre-treatment 
* 
 
 
 
 
 
Cycle 1 
 
 
 
 
Cycle 2 
 
 
 
Cycle 3 
** 
 
 
Cycle 4 
 
 
 
 
Cycle 7 
** 
 
 
 
Cycle 10 
** 
 
 
 
End of treatment 
*** 
 
 
 
 
 
 
7.7 
Quality of Life Assessment  
 
HRQoL questionnaires (Appendix 5) will be completed in order to establish how PS2 patients 
are coping with trial treatment. Patients will be asked to complete a questionnaire before 
every cycle of pembrolizumab. The Research Nurse should spend time with the patient going 
through the questionnaire and answering any questions patients might have at cycle 1. 
Thereafter the patient should then answer the questionnaire independently then return it the 
Research Nurse. 
 
7.8 
Treatment Compliance 
 
Treatment compliance will be based on patient attendance to scheduled clinic visits as 
pembrolizumab will be administered in these sessions. 
 
7.9 
Concomitant Medication 
 Acceptable Concomitant Medications 
7.9.1
 
Throughout the trial any concomitant medication or therapy deemed necessary to provide 
adequate supportive care may be prescribed and should be recorded within the Case Report 
Form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids. The indication for the treatment should be recorded at the same time.  
If changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date will also be included on the CRF. 
 
All concomitant medications received within 28 days of Trial Entry and 30 days after the last 
dose of trial treatment should be recorded. Concomitant medications administered after 30 
  * pre-registration, pre-treatment baseline biopsy (fresh if  no archive is available) 
 ** only 10 ml required 
*** optional newly obtained biopsy 

 
 
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days after the last dose of trial treatment should be recorded for Serious Adverse Events 
(SAEs). 
 Prohibited Concomitant Medications 
7.9.2
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy within 28 days prior to the first 
dose of trial treatment and while participating in the trial. 
• Immunotherapy not specified in this protocol. 
• Chemotherapy not specified in this protocol. 
• Investigational agents other than pembrolizumab. 
• Radiation therapy 
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with the Trials Office. Recommencement of trial treatment 
after radiation therapy will be at the discretion of the PI after consultation with the 
PePS2 Trial Office. 
• 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 etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the PePS2 Trial Office. 
• Whilst participating on the trial, patients may be given systemic steroids due to an acute 
medical situation but the steroids may only be given for a maximum of 2 weeks. During 
this period, trial treatment must stop and can be restarted when the steroid 
administration is complete. If the subject requires the continued use of steroid treatment 
for more than 2 weeks, they should be withdrawn from the trial. 
• Any form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment and while participating on the trial. Replacement therapy (e.g. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
 
Subjects who, on the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be withdrawn from the trial. 
Subjects may receive other medications that the Investigator deems to be medically 
necessary. 
There are no prohibited therapies during the post-treatment follow-up phase. 
7.10 Patient Follow up 
 
After a patient is discontinued from trial therapy, a mandatory safety follow-up visit should be 
performed 28 days after the last infusion of trial medication. Procedures and assessments 

 
 
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performed at the safety follow-up visit should follow the respective guidelines described in 
the Schedule of Events. The patient will be monitored for all AEs monthly for up to 6 months 
and then 12 weekly during long term follow up. 
 
For patients who start another cancer therapy before 28 days after discontinuation of trial 
therapy, the safety follow-up visit should occur prior to the patient receiving another cancer 
therapy. Follow up calls will be made every 12 weeks to record treatment after progression 
and death date if applicable. 
 
7.11 Patient Withdrawal 
 
The Investigator will make every reasonable effort to keep each patient on trial. However, if 
the Investigator removes a patient from the trial treatment or if (s)he declines further 
participation final assessments will be performed, if possible. All the results of the evaluations 
and observations, together with a description of the reasons for trial withdrawal, must be 
recorded in the CRF. For patients withdrawing from trial treatment for reasons other than 
withdrawal of consent or due to disease progression then continue with RECIST 1.1 scans 
until documented progression as per protocol. For patients who have come off treatment due 
to unacceptable toxicity, CT scans will be performed every 9 weeks until disease progression 
or until the patient starts another anti-cancer treatment. CT scans are to be reported 
according to RECIST v1.1 criteria (see Appendix 2). 
 
Following assessment by the Principal Investigator and discussion with the PePS2 Trial 
Office, patients who meet RECIST criteria for progressive disease (PD) may be continued on 
trial treatment if the treatment is tolerable and believed to be of clinical benefit.  
Documentation of continued clinical benefit should be recorded in the patient’s medical notes 
by an Investigator. 
 
In the event of a patient’s decision to withdraw from the trial, the Investigator must ascertain 
from which aspects of the trial the patient wishes to withdraw, and record the details on the 
Withdrawal CRF. All patients will continue to be followed-up, and all information and tissue 
samples collected up until the point of withdrawal, will be retained and analysed. 
 
Patients who withdraw from the trial due to AEs (clinical or laboratory) will be treated and 
followed according to accepted medical practice. All pertinent information concerning the 
outcome of such treatment must be recorded in the CRF. 
 
The following are justifiable reasons for the Investigator to withdraw a patient from trial:  
• Unacceptable toxicity 
• Unforeseen events: any event which in the judgement of the Investigator makes further 
treatment inadvisable 
• SAE requiring discontinuation of treatment 
• Withdrawal of consent 
• Serious violation of the trial protocol (including persistent patient attendance failure and 
persistent non-compliance) 
• Withdrawal by the Investigator for clinical reasons not related to the trial drug treatment 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the Investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the Investigator or the Sponsor if enrolment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding discontinuation are provided in Section 7.5. 

 
 
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An evaluable patient is a patient who receives treatment with pembrolizumab. Where a 
patient is withdrawn from the trial and is not evaluable, an additional patient will be recruited 
to replace them. 
 
7.12 Expected Toxicity, Rescue Medications and Supportive Care 
 Management of Infusion Reactions 
7.12.1
 
Pembrolizumab may cause severe or life threatening infusion-reactions. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab associated infusion reaction are provided in 
Table 6. 
 

 
 
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Table 6: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
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 
subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
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 
subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 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 subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Subject may be premedicated 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 analgesic). 

 
 
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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; 
hospitalization 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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Subject is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside 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 
 

 
 
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8 
TRANSLATIONAL RESEARCH ASSOCIATED WITH THE PEPS2 TRIAL 
 
Exploratory outcomes will be based on the identification of possible biomarkers predictive of 
response to pembrolizumab. We will analyse blood and stool samples to identify possible 
biomarkers of response. This will be a purely discovery analysis and new putative 
biomarkers would require prospective validation. 
 
9 
ADVERSE EVENT REPORTING 
 
The collection and reporting of AEs will be in accordance with the Medicines for Human Use 
Clinical Trials Regulations 2004 and its subsequent amendments. Definitions of different 
types of AE are listed in Appendix 7. The Investigator should assess the seriousness and 
causality (relatedness) of all AEs experienced by the patient (this should be documented in 
the source data) with reference to the SPC. 
9.1 
Reporting Requirements 
 Adverse Events 
9.1.1
 
All medical occurrences which meet the definition of an AE (see Appendix 7 for definition) 
should be reported. Please note this includes abnormal laboratory findings that are deemed 
clinically significant by the Investigator (abnormal laboratory findings that are not clinically 
significant are not AEs) or any pre-existing AEs that worsen by at least 1 CTCAE grade from 
baseline. If an AE changes grade, this should be reported as an individual AE. 
 Serious Adverse Events 
9.1.2
 
Investigators should report AEs that meet the definition of an SAE (see Appendix 7 for 
definition) as detailed in Section 8.2. 
 
9.1.2.1 Monitoring pregnancies for potential Serious Adverse Events 
 
It is important to monitor the outcome of pregnancies of patients in order to provide SAE data 
on congenital anomalies or birth defects. 
 
In the event that a patient or their partner becomes pregnant during the SAE reporting period 
please complete a Pregnancy Notification Form (providing the patient’s details) and return to 
the PePS2 Trial Office as soon as possible. If it is the patient who is pregnant, provide 
outcome data on a follow-up Pregnancy Notification Form. Where the patient’s partner is 
pregnant, consent must first be obtained and the patient should be given a Release of 
Medical Information Form to give to their partner. If the partner is happy to provide 
information on the outcome of their pregnancy they should sign the Release of Medical 
Information Form. Once consent has been obtained, provide details of the outcome of the 
pregnancy on a follow-up Pregnancy Notification Form. If appropriate also complete an SAE 
Form as detailed below. 
 Events of Clinical Interest 
9.1.3
 
Selected non-serious AEs and SAEs are also known as Events of Clinical Interest (ECI). This 
also includes immune-mediated AEs (see Appendix 7 for more details). Events of clinical 
interest for this trial include: 

 
 
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1. An overdose of pembrolizumab. For purposes of this trial, an overdose of pembrolizumab 
will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose).  No 
specific information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the event of 
overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
 
* Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. 
 
 Reporting period 
9.1.4
 
Details of all treatment-related AEs will be documented and reported from the date of patient 
registration until 6 months after the administration of the last treatment. SAEs that are judged 
to be at least possibly related to IMP must still be reported in an expedited manner 
irrespective of how long after IMP administration the reaction occurred. 
9.2 
Reporting Procedure 
 Site 
9.2.1
9.2.1.1 Adverse Events 
 
AEs should be reported on an AE Form (and where applicable on an SAE Form). An AE 
Form should be completed at each visit and returned to the PePS2 Trial Office. 
 
AEs will be reviewed using the Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0 (see Appendix 6). Any AEs experienced by the patient but not included in the 
CTCAE should be graded by an Investigator and recorded on the AE Form using a scale of 
(1) mild, (2) moderate or (3) severe. For each sign/symptom, any changes in grade should 
be documented. 
 
9.2.1.2 Serious Adverse Events 
 
For more detailed instructions on Serious Adverse Event (SAE) reporting refer to the SAE 
Form Completion Guidelines contained in section 5 of the ISF. 
 
AEs defined as serious and which require reporting as an SAE should be reported on an 
SAE Form. When completing the form, the Investigator will be asked to define the causality 
and the severity of the AE which should be documented using the CTCAE version 4.0. 
 
On becoming aware that a patient has experienced an SAE, the Investigator (or delegate) 
must complete, date and sign an SAE Form. The form should be faxed together with a SAE 
Fax Cover Sheet to the PePS2 Trial Office using one of the numbers listed below as soon as 
possible and no later than 24 hours after first becoming aware of the event: 

 
 
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To report an SAE, fax the SAE Form with an SAE Fax Cover Sheet to: 
0121 414 3529 (primary) or 0121 414 7989 (secondary) 
On receipt the PePS2 Trial Office will allocate each SAE a unique reference number. This 
number will be transcribed onto the SAE Fax Cover Sheet which will then be faxed back to 
the site as proof of receipt. If confirmation of receipt is not received within 1 working day 
please contact the PePS2 Trial Office. The SAE reference number should be quoted on all 
correspondence and follow-up reports regarding the SAE. The SAE Fax Cover Sheet 
completed by the PePS2 Trial Office should be filed with the SAE Form in the ISF. 
 
For SAE Forms completed by someone other than the Investigator, the Investigator will be 
required to countersign the original SAE Form to confirm agreement with the causality and 
severity assessments. The form should then be returned to the PePS2 Trial Office in the post 
and a copy kept in the ISF. Investigators should also report SAEs to their own Trust in 
accordance with local practice. 
 
9.2.1.3 Events of Clinical Interest 
 
ECI must be reported within 24 hours to the PePS2 Trial Office. For the time period 
beginning when the consent form is signed until treatment allocation, any ECI, or follow up to 
an ECI, that occurs to any subject must be reported within 24 hours to the PePS2 Trial Office 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet or a 
procedure. 
For the time period beginning at treatment allocation through 6 months following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to 
pembrolizumab, must be reported within 24 hours to the Trial Office. 
 
9.2.1.4 Provision of Follow-up Information 
 
Patients should be followed up until resolution or stabilisation of the Follow-up information 
should be provided on a new SAE Form (refer to the SAE Form Completion Guidelines for 
further information). 
 
 PePS2 Trial Office 
9.2.2
 
On receipt of an SAE Form, seriousness and causality will be determined independently by a 
Clinical Coordinator. An SAE judged by the Investigator or Clinical Coordinator to have a 
reasonable causal relationship with the trial medication will be regarded as a Serious 
Adverse Reaction (SAR). The Clinical Coordinator will also assess all SARs for 
expectedness. If the event meets the definition of a SAR that is unexpected (i.e. is not 
defined in the Reference Safety Information) it will be classified as a Suspected Unexpected 
Serious Adverse Reaction (SUSAR). 
 
 

 
 
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 Reporting to the Competent Authority and Research Ethics Committee 
9.2.3
9.2.3.1 Suspected Unexpected Serious Adverse Reactions 
 
The PePS2 Trial Office will report a minimal data set of all individual events categorised as a 
fatal or life threatening SUSAR to the Medicines and Healthcare products Regulatory Agency 
(MHRA) and Research Ethics Committee (REC) within 7 days. Detailed follow-up information 
will be provided within an additional 8 days. 
 
All other events categorised as SUSARs will be reported within 15 days. 
9.2.3.2 Serious Adverse Reactions 
 
The PePS2 Trial Office will report details of all SARs (including SUSARs) to the MHRA and 
main REC annually from the date of the Clinical Trial Authorisation, in the form of a 
Developmental Safety Update Report. 
9.2.3.3 Adverse Events 
 
Details of all AEs will be reported to the MHRA on request. 
9.2.3.4 Other safety issues identified during the course of the trial 
 
The MHRA and REC will be notified immediately if a significant safety issue is identified 
during the course of the trial. 
 
 Investigators 
9.2.4
 
Details of all SUSARs and any other safety issue which arises during the course of the trial 
will be reported to Principal Investigators. A copy of any such correspondence should be filed 
in the ISF.  
 
 Trial Steering Committee 
9.2.5
 
The Trial Steering Committee will review all SAEs. 
 
 Manufacturer of Investigational Medicinal Product 
9.2.6
 
All SAEs will be reported to Merck, Sharp and Dohme, the manufacturer of the 
Investigational Medicinal Product, within an agreed timeframe from first awareness of the 
event of the PePS2 Trial Office during the reporting period.  
 
10 DATA HANDLING AND RECORD KEEPING 
10.1 Data Collection 
 Case Report Form (CRF) 
10.1.1
 
The CRF will comprise a set of forms capturing details of eligibility, baseline characteristics, 
treatment and outcome details. This trial will use an electronic remote data capture (eRDC) 

 
 
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system which will be used for completion of CRF. Access to the eRDC system will be 
granted to individuals via the Trial Office. Pre-screening Registration, SAE reporting and 
Notification of Pregnancy will be paper-based. 
 
The CRF must be completed by the Investigator or an authorised member of the site 
research team (as delegated on the Site Signature and Delegation Log) within specified 
timeframes (found in the CRF completion guidelines). The exceptions to this are the SAE 
Form, which must be co-signed by the Investigator and reported in an expedited manner. 
 
Data reported on each form should be consistent with the source data or the discrepancies 
should be explained. If information is not known, this must be clearly indicated on the form. 
All missing and ambiguous data will be queried. All sections are to be completed. CRF 
guidelines will be provided. In all cases it remains the responsibility of the Investigator to 
ensure that the CRF has been completed correctly and that the data are accurate. 
 
The format and questions in the CRF may be amended by the Trial Office, as appropriate, 
throughout the duration of the trial. Whilst this will not constitute a protocol amendment, sites 
will be notified of new versions of the form when they are available in the eRDC system, and 
in the case of the SAE form, new versions of the form must be implemented by participating 
sites immediately on receipt. 
10.2 Archiving 
 
It is the responsibility of the Principal Investigator to ensure all essential trial documentation 
and source records (e.g. signed Informed Consent Forms, Investigator Site Files, Pharmacy 
Files, patients’ hospital notes, copies of CRFs etc.) at their site are securely retained for at 
least 25 years after the end of the trial or following the processing of all biological material 
collected for research, whichever is the later. Do not destroy any documents without prior 
approval from the PePS2 Trial Office. 
 
11 QUALITY MANAGEMENT 
11.1 Site Set-up and Initiation 
 
All sites will be required to sign a Clinical Trial Site Agreement prior to participation. In 
addition all participating Investigators will be asked to sign the necessary agreements and 
registration forms; and supply a current CV to the PePS2 Trial Office. All members of the site 
research team will also be required to sign the Site Signature and Delegation Log, which 
should be returned to the PePS2 Trial Office. Prior to commencing recruitment all sites will 
undergo a process of initiation. Key members of the site research team will be required to 
attend either a meeting or a teleconference covering aspects of the trial design, protocol 
procedures, AE reporting, collection and reporting of data and record keeping. Sites will be 
provided with an Investigator Site File and a Pharmacy File containing essential 
documentation, instructions, and other documentation required for the conduct of the trial.  
 
The PePS2 Trial Office must be informed immediately of any change in the site research 
team. 
11.2 On-site Monitoring 
 
Monitoring will be carried out as required following a risk assessment and as documented in 
the CRCTU Quality Management Plan. Additional on-site monitoring visits may be triggered 
for example by poor CRF return, poor data quality, low SAE reporting rates, excessive 

 
 
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number of patient withdrawals or deviations. If a monitoring visit is required the PePS2 Trial 
Office will contact the site to arrange a date for the proposed visit and will provide the site 
with written confirmation. Investigators will allow the PePS2 trial staff access to source 
documents as requested. 
 
11.3 Central Monitoring 
 
Trial staff will be in regular contact with the site research team to check on progress and 
address any queries that they may have. Trial staff will check incoming data entered onto the 
PePS2 eRDC for compliance with the protocol, data consistency, missing data and timing. 
Sites will be sent electronic Data Clarification Forms requesting missing data or clarification 
of inconsistencies or discrepancies. Where a patient has given explicit consent sites are 
requested to send in copies of signed Informed Consent Forms for in-house review. 
 
Sites may be suspended from further recruitment in the event of serious and persistent non-
compliance with the protocol and/or good clinical practice (GCP), and/or poor recruitment. 
Any major problems identified during monitoring may be reported to the Trial Management 
Group and the relevant regulatory bodies. This includes reporting serious breaches of GCP 
and/or the trial protocol to the REC and MHRA. 
11.4 Audit and Inspection 
 
The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory 
inspection(s) at their site, providing direct access to source data/documents. 
 
Sites are also requested to notify the PePS2 Trial Office of any MHRA inspections. 
 
11.5 Notification of Serious Breaches 
 
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and its amendments the Sponsor of the trial is responsible for notifying the 
licensing authority in writing of any serious breach of: 
• The conditions and principles of GCP in connection with that trial or; 
• The protocol relating to that trial, within 7 days of becoming aware of that breach 
 
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a 
significant degree: 
• The safety or physical or mental integrity of the subjects of the trial; or 
• The scientific value of the trial 
 
Sites are therefore requested to notify the PePS2 Trial Office of a suspected trial-related 
serious breach of GCP and/or the trial protocol. Where the PePS2 Trial Office is investigating 
whether or not a serious breach has occurred sites are also requested to cooperate with the 
PePS2 Trial Office in providing sufficient information to report the breach to the MHRA where 
required and in undertaking any corrective and/or preventive action. 
 
 

 
 
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12 END OF TRIAL DEFINITION 
 
The end of trial will be 6 months after the last data capture. This will allow sufficient time for 
the completion of protocol procedures, data collection and data input. The PePS2 Trial Office 
will notify the MHRA and REC that the trial has ended and will provide them with a summary 
of the clinical trial report within 12 months of the end of trial. 
 
13 STATISTICAL CONSIDERATIONS 
13.1 Definition and Calculation of Outcome Measures 
 Primary Outcomes 
13.1.1
The trial design is based on two co-primary outcome measures representing toxicity and 
efficacy. The toxicity co-primary outcome measure for the trial is defined as the occurrence of 
a treatment-related dose delay or treatment discontinuation due to an adverse event. 
Patients will have CT scans every 9 weeks from baseline until disease progression. On each 
occasion, overall tumour burden will be assessed using RECIST 1.1, according to the study 
protocol. The efficacy co-primary outcome measure for the trial is durable clinical benefit, 
defined as the occurrence of of a complete response (CR), partial response (PR) or stable 
disease (SD) without prior progressive disease (PD) at or after the second scheduled CT 
scan (scheduled to occur at18 weeks). 
 
For example, a disease response of (CR / PR / SD) at 9 weeks, followed by a disease 
response of (CR / PR / SD) at 18 weeks would constitute efficacy. Likewise, (CR / PR / SD) 
at 9 weeks, missing data at 18 weeks, and (CR / PR / SD) at 27 weeks would also constitute 
efficacy. Patients for whom the primary efficacy outcome could not be determined will be 
taken as not experiencing durable clinical benefit. 
 Secondary Outcomes 
13.1.2
13.1.2.1  Objective Response (OR) 
Best overall response is the best response recorded over the whole period of assessment 
and could be complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD) or inevaluable for response (NA, for which reasons such as early 
death due to disease or early death due to toxicity will be specified). Objective response 
(OR) is the occurrence of CR or PR as the best overall response. OR will be based on 
responses confirmed using the subsequent 9-weekly scan but OR based on unconfirmed 
responses will also be reported. 
13.1.2.2 Health Related Quality of Life (HRQoL) 
The purpose of HRQoL measurement is to quantify the degree to which the medical 
condition or its treatment impacts the individual’s life in a valid and reproducible way. Health-
related quality-of-life will be measured using the FACT-L and EQ-5D questionnaires, and a 
patient-generated subjective global assessment questionnaire, as identified in the protocol 
(see Appendix 5 for questionnaires). The FACT-L questionnaire generates 5 measures for 
analysis: physical well-being, social/family well-being, emotional well-being, functional well-
being and the lung cancer subscale. The EQ5D questionnaire generates 2 measures for 
analysis: an EQ5D utility measure and an EQ5D Visual Analogue Scale. Questionnaires will 
be administered on day 1 of every cycle prior to receiving treatment and also at the end of 
treatment visit. 

 
 
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13.1.2.3 Time to Progression (TTP) 
This is defined as the time from commencement of trial treatment to the date of CT scan 
when progressive disease is first recorded. Patients with no recorded progression at the time 
of analysis or who die without recorded progression will be censored at the date of the CT 
scan when they were last recorded with an evaluable measure that was not progression. 
13.1.2.4 Progression-Free Survival Time (PFS) 
This is defined as the time from commencement of trial treatment to the date of CT scan 
when progressive disease first recorded or date of death without previously recorded 
progression. Patients who are alive with no recorded progression at the time of analysis will 
be censored at the date of the CT scan when they were last recorded with an evaluable 
measure that was not progression. 
13.1.2.5 Overall Survival Time (OS) 
This is defined as the time from commencement of trial treatment to the date of death. 
Patients who are alive at the time of analysis will be censored at the date last confirmed 
alive. 
13.1.2.6 Duration of Objective Response (DOR) and Duration of Stable Disease (DSD) 
Duration of objective response and duration of stable disease are defined as the time from 
commencement of trial treatment to the date of the subsequent CT scan when progressive 
disease is first confirmed or date of death without previously recorded progression. This 
outcome will be calculated and reported separately for patients who achieve an OR or SD. 
Patients experiencing OR or SD who are alive with no recorded progression at the time of 
analysis will be censored at the date of the CT scan when they were last recorded with an 
evaluable measure that was not progression. 
 
13.2 Methods of Analysis 
 Primary Outcomes 
13.2.1
The co-primary outcomes will be summarised as toxicity rate and durable clinical benefit rate 
and analysed simultaneously using the BEBOP (Bayesian Evaluation of Binary Outcomes 
with Predictive variables) method, developed by Brock, et al. (publication forthcoming). 
 
Each patient will have a PD-L1 proportion score and this will determine membership to one 
of three PD-L1 categories, shown in Table 7. These categories were validated to be 
predictive of response in Garon, et al (19). Additionally, each patient will be either previously 
treated or not previously treated. These two variables yield the six PePS2 cohorts shown in 
Table 8. 
Table 7: A patient’s PD-L1 category is inferred from their PD-L1 proportion score 
Criteria on PD-L1 proportion score z 
PD-L1 category 
z < 1% 
Low 
1% ≤ z < 50% 
Medium 
z ≥ 50% 
High 
 
 

 
 
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Table 8: PePS2 cohorts and corresponding vectors of predictive values, x = (x1, x2, x3) 
Cohort 
Treatment status 
PD-L1 category 
x1 
x2 
x3 
1 
Not pre-treated 
Low 
0 
1 
0 
2 
Not pre-treated 
Medium 
0 
0 
1 
3 
Not pre-treated 
High 
0 
0 
0 
4 
Pre-treated 
Low 
1 
1 
0 
5 
Pre-treated 
Medium 
1 
0 
1 
6 
Pre-treated 
High 
1 
0 
0 
 
Let 𝜃= (𝛼, 𝛽, 𝛾, 𝜁, 𝜆, 𝜓) be a vector of parameters. We model the marginal probability of 
efficacy in patients with the predictive values x = (x1, x2, x3) using the logit-model 
 
𝜋𝐸(𝒙, 𝜃) = 𝛼+ 𝛽𝑥1 + 𝛾𝑥2 + 𝜁𝑥3 
 
and the marginal probability of toxicity using the logit-model 
 
𝜋𝑇(𝒙, 𝜃) = 𝜆 
 
Using these formulae, the probability of efficacy is different for each cohort. In contrast, the 
probability of toxicity is uniform across the cohorts. These assumptions are supported by 
data published on similar studies in performance status 0 and 1 patients.  
 
Let a=1 for a given patient if they experience efficacy, and b=1 if they experience toxicity. 
The joint probability density of efficacy and toxicity events for this patient is modelled using 
the formula 
 
𝜋𝑎,𝑏= 𝜋𝐸
𝑎(1 −𝜋𝐸)(1−𝑎)𝜋𝑇
𝑏(1 −𝜋𝑇)(1−𝑏) + (−1)𝑎+𝑏𝜋𝐸(1 −𝜋𝐸)𝜋𝑇(1 −𝜋𝑇)  𝑒𝜓−1
𝑒𝜓+ 1 
 
The fraction on the right-hand side, which ranges in value over (-1, 1) for 𝜓∈(∞, −∞), 
models the association between efficacy and toxicity events. 
 
Let 𝑿= {(𝒙1, 𝑎1, 𝑏1), … , (𝒙𝑛, 𝑎𝑛, 𝑏𝑛)} be the trial outcomes for n patients. The aggregate 
likelihood function is 
 
𝐿(𝑿, 𝜃) = ෑ𝜋𝑎𝑖,𝑏𝑖  (𝒙𝑖, 𝜃)
𝑛
𝑖=1
 
 
With prior f(θ), the posterior distribution, up to proportionality, is  
 
𝑓(𝜃|𝑋) ∝ 𝑓(𝜃)  𝐿(𝑿, 𝜃) 
 
We use normal prior distributions for the elements of θ with means and variances given in 
Table 9. These give prior events rates of approximately 20% for efficacy and toxicity in each 
cohort. This can be verified by setting 𝑿= { } and estimating the ‘posterior’ probabilities of 
efficacy and toxicity. The prior event rates we use represent conservative extrapolations of 
those published in performance status 0 & 1 patients, where, if we were to anticipate a 

 
 
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difference compared to our performance status 2 population, the stronger PS=0/1 patients 
would be more likely to achieve response and less likely to experience toxicity. 
Table 9: Parameters for normal prior distributions for the elements of θ 
Parameter 
Mean 
Variance 
α 
-2.2 
4 
β 
-0.5 
4 
γ 
-0.5 
4 
ζ 
-0.5 
4 
λ 
-2.2 
4 
ψ 
0 
1 
 
The EffTox software estimates the effective sample size of these priors to be equivalent to 
the outcomes of 1.32 patients, thus the priors may be considered to be weakly informative. 
 
Given trial data X, inferences on θ and functions of θ, such as 𝜋𝐸(𝒙, 𝜃) and 𝜋𝑇(𝒙, 𝜃), are 
made using the posterior probability measure. This requires solving integrals of dimension 
equal to the number of elements in θ. Generally, this is done numerically rather than 
analytically using software, described in the Statistical Analysis Plan (SAP). 
 
Pembrolizumab will be considered successful in cohort i with the corresponding predictive 
vector xi taken from Table 8 if 
 
Pr(𝜋𝐸(𝒙𝑖, 𝜃) >  0.1 | 𝑿) > 0.7 
and 
 
Pr(𝜋𝑇(𝒙𝑖, 𝜃) <  0.3 | 𝑿) > 0.9 
 
That is, we want to be 70% certain a-posteriori that the efficacy rate exceeds 10% and 90% 
certain that the toxicity rate is less than 30%, to approve the treatment in a given cohort. 
Separate decisions will be made for each cohort. The hurdle rates for efficacy and toxicity 
were chosen for their clinical relevance by considering the equivalent rates associated with 
alternative treatments that these patients might receive. The certainty rates were chosen to 
give good operating performance with the identified sample size, described in the SAP. 
 Secondary Outcomes 
13.2.2
13.2.2.1 Time-to-event outcomes 
Time-to-event outcomes (TTP, PFS, OS, DOR, DSD) will be analysed using the Kaplan-
Meier method. Median time-to-event (and 90% CIs) will be presented for each outcome. 
Milestone events rates will be presented (with 90% CIs) for each outcome. Milestone rates 
will be presented at appropriate times, selecting from 3, 6, 12, 18 and 24 months. Note 
that 90% confidence intervals are appropriate in this single arm phase II trial. 
13.2.2.2 Binary outcomes 
Binary outcomes (OR) will be reported as a numerator, a denominator, a rate and a 90% 
confidence interval calculated using Wilson’s method. 

 
 
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13.2.2.3 HRQoL outcomes 
Descriptive longitudinal analyses of each quality of life score will be presented. If 
appropriate, the EQ5D utility score may be combined with the survival data to estimate 
quality-adjusted life years using the integrated quality-survival product (27). 
The PePS2 SAP presents full details on the analysis method, including assessment of the 
BEBOP method by simulation study, and proposed exploratory analyses. 
 
14 TRIAL ORGANISATIONAL STRUCTURE 
14.1 Sponsor 
 
The trial sponsor is the University of Birmingham. 
14.2 Coordinating Centre 
 
The trial is being conducted under the auspices of the Cancer Research UK Clinical Trials 
Unit (CRCTU), University of Birmingham according to their local procedures. 
14.3 Trial Management Group 
 
A Trial Management Group (TMG) will be established and as a minimum will include the 
Chief Investigator, Co-Investigators, the Lead and Trial Statistician, Trial Management Team 
Leader and Trial Coordinator. Other key personnel may be invited to join the TMG as 
appropriate to ensure representation from a range of professional groups. Notwithstanding 
the legal obligations of the Sponsor and Chief Investigator, the TMG will be responsible for 
the day-to-day running and management of the trial and will meet by teleconference or in 
person as required. 
 
14.4 Trial Steering Committe 
 
The role of the Trial Steering Committee (TSC) is to provide oversight of the trial on behalf of 
the Sponsor (University of Birmingham) and to ensure that the trial is conducted to the 
rigorous standards set out in the GCP standards. In particular, the TSC will concentrate on 
progress of the trial, adherence to the protocol, patient safety and the consideration of new 
information of relevance to the research question(s). The safety and well-being of the trial 
participants are the most important considerations and should prevail over the interests of 
the science and society. 
The TSC will provide advice, through its chair, to the Chief Investigator and the University of 
Birmingham on all appropriate aspects of the trial. The TSC will be asked to comment in 
detail on substantial changes to protocol. The TSC will meet at least once per year during 
recruitment. 
14.5 Finance 
 
This is an Investigator-initiated and Investigator-led trial funded by Merck, Sharp and Dohme. 
 
The trial has been independently peer reviewed and has been adopted by the National 
Institute for Health Research (NIHR) Clinical Research Network (CRN) Portfolio. 

 
 
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15 ETHICAL CONSIDERATIONS 
 
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects, adopted by the 18th World Medical 
Association General Assembly, Helsinki, Finland, June 1964, amended at the 48th World 
Medical Association General Assembly, Somerset West, Republic of South Africa, October 
1996 (website: http://www.wma.net/en/30publications/10policies/b3/index.html) (Appendix 8). 
 
The trial will be conducted in accordance with the UK Policy Framework for Health and 
Social Care Research, the applicable UK Statutory Instruments, (which include the 
Medicines for Human Use Clinical Trials 2004 and subsequent amendments and the Data 
Protection Act 1998 and Human Tissue Act 2008) and GCP. This trial will be carried out 
under a Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical 
Trials regulations. The protocol will be submitted to and approved by the REC prior to 
circulation.  
 
Before any patients are enrolled into the trial, the Principal Investigator at each site is 
required to obtain local R&D approval. Sites will not be permitted to enrol patients until 
written confirmation of R&D approval is received by the PePS2Trial Office.  
 
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments 
gain the necessary local approval. This does not affect the individual clinicians’ responsibility 
to take immediate action if thought necessary to protect the health and interest of individual 
patients. 
 
16 CONFIDENTIALITY AND DATA PROTECTION 
 
Personal data recorded on all documents will be regarded as strictly confidential and will be 
handled and stored in accordance with the General Data Protection Regulation 2016/679 
and the Data Protection Act 2018. With the patient’s consent, their full name, date of birth, 
hospital number, general practitioner details will be collected at trial entry to allow tracing 
through the Cancer Registries and the NHS Information Centre for Health and Social Care 
(service formally provided by the Office of National Statistics) and to assist with long-term 
follow-up via other health care professionals (e.g. patient’s GP). Patients will be identified 
using only their unique Trial Number and initials on both electronic and paper CRF and 
correspondence between the PePS2 Trial Office and the participating site. However patients 
are asked to give permission for the PePS2 Trial Office to be sent a copy of their signed 
Informed Consent Form which will not be anonymised. This will be used to perform in-house 
monitoring of the consent process. The Investigator must maintain documents not for 
submission to the PePS2 Trial Office (e.g. Patient Identification Logs) in strict confidence. In 
the case of specific issues and/or queries from the regulatory authorities, it will be necessary 
to have access to the complete trial records, provided that patient confidentiality is protected.  
 
The PePS2 Trial Office will maintain the confidentiality of all patients’ data and will not 
disclose information by which patients may be identified to any third party other than those 
directly involved in the treatment of the patient and organisations for which the patient has 
given explicit consent for data transfer (e.g. Cancer Registries). Representatives of the 
PePS2 trial team may be required to have access to patient’s notes for quality assurance 
purposes but patients should be reassured that their confidentiality will be respected at all 
times. 
 

 
 
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17 INSURANCE AND INDEMNITY 
 
In terms of liability at a site, NHS Trust and non-Trust hospitals have a duty to care for 
patients treated, whether or not the patient is taking part in a clinical trial. Compensation is 
therefore available via NHS indemnity in the event of clinical negligence having been proven. 
University of Birmingham employees are indemnified by the University insurers for negligent 
harm caused by the design or co-ordination of the clinical trials they undertake whilst in the 
University’s employment. The University of Birmingham cannot offer indemnity for non-
negligent harm. The University of Birmingham is independent of any pharmaceutical 
company, and as such it is not covered by the Association of the British Pharmaceutical 
Industry (ABPI) guidelines for patient compensation. 
 
18 PUBLICATION POLICY 
 
Results will be submitted for publication in a peer reviewed journal. The manuscript will be 
prepared by the TMG and authorship will be determined by mutual agreement. 
 
Any secondary publications and presentations prepared by Investigators must be reviewed 
by the TMG and Merck, Sharpe, Dohme. Manuscripts must be submitted in a timely fashion 
and in advance of being submitted for publication, to allow time for review and resolution of 
any outstanding issues. Authors must acknowledge that the trial was performed with the 
support of the University of Birmingham. Intellectual property rights will be addressed in the 
Clinical Trial Site Agreement between Sponsor and site. 
 
 

 
 
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Lubiniecki, Jin Zhang, Michelle Niewood, Kenneth Emancipator, Marisa Dolled-Filhart, Mary 
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Rao, Katsuyuki Hotta, Melanie A. Leiby, Gregory M. Lubiniecki, Yue Shentu, Reshma 
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Majem, Mary J Fidler, Gilberto de Castro Jr, Marcelo Garrido, Gregory M Lubiniecki, Yue 
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23. 
Lilenbaum R, Axelrod R, Thomas S, Dowlati A, Seigel L, Albert D, et al. Randomized 
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25. 
Dajczman E, Kasymjanova G, Kreisman H, Swinton N, Pepe C, Small D. Should 
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26. 
Ando M, Ando Y, Hasegawa Y, Shimokata K, Minami H, Wakai K, et al. Prognostic 
value of performance status assessed by patients themselves, nurses, and oncologists in 
advanced non-small cell lung cancer. British journal of cancer. 2001;85(11):1634-9. 
27. 
Billingham LJ and KR Abrams. Simultaneous analysis of quality of life and survival 
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28. 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982; 5:649-655. 
29. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
30. 
Charlson, ME., Popei, P., Ales KL, MacKenzie CR., (1987). “A new method of 
classifying prognostic comorbidity in longitudinal studies: Development and validation”. 
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Ottery FD (2000): Patient-Generated Subjective Global Assessment. In: The Clinical 
Guide to Oncology Nutrition, ed. PD McCallum & CG Polisena, pp 11–23. Chicago: The 
American Dietetic Association 

 
 
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APPENDICES 
Appendix 1: Eastern Cooperative Oncology Group Performance Status Criteria (28) 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
 
 

 
 
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Appendix 2: RECIST v1.1 criteria 
RECIST version 1.1 will be used in this trial for assessment of tumour response. While either 
CT or MRI may be used, as per RECIST 1.1, CT is the preferred imaging technique in this 
trial. 
 
The following contains excerpts from the RECIST version 1.1 plus trial specific instructions. 
A 
free 
copy 
of 
the 
revised 
guidelines 
is 
available 
from 
http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf (29) 
 
Measurability of Tumour Lesions at Baseline 
 
Only patients with measurable disease at baseline should be included. Measurable disease 
is defined by the presence of at least one measurable lesion. At baseline, tumour lesions will 
be categorised as follows: 
• Measurable 
• Non-measurable 
Measurable lesions are those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) with a minimum size of 10 mm by CT scan (CT scan slice 
thickness no greater than 5 mm), 10 mm calliper measurement by clinical exam (lesions 
which cannot be accurately measured with callipers should be recorded as non-measurable) 
and 20 mm by chest X-ray. For malignant lymph nodes to be considered pathologically 
enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by a 
CT scan (at baseline and during treatment, only the short axis will be measured and 
followed). 
 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥10 to >15 mm short axis) and truly non-measurable 
lesions. 
Lesions considered to be truly non-measurable include the following: bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by 
imaging techniques, and cystic lesions. 
 
Tumour lesions that are situated in a previously irradiated area are not considered 
measurable. 
The term "evaluable" in reference to measurability is not recommended and will not be used 
because it does not provide additional meaning or accuracy. 
 
All measurements should be recorded in metric notation using callipers (or a ruler) if clinically 
assessed. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of treatment. 
 
Specifications by Methods of Measurements 
 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesions at baseline, during treatment and at the post-treatment 
assessment. Image-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the anti-tumour effect of a treatment. CT is the best 
currently available and reproducible method for measuring target lesions selected for 
response assessment. Investigators should utilize the best available CT imaging technique 
available to them for determining response and PFS of patients participating in the PePS2 
trial. 

 
 
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Tumour Response Evaluation 
 
Baseline Documentation of "Target" and "Non-target" Lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as “target” lesions and recorded 
and measured at baseline. 
 
Target lesions should be selected on the basis of their size (those with the longest diameter) 
and their suitability for accurate, reproducible, repeated measurements. 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as the reference by which to 
characterise the objective tumour response. 
 
All other lesions (or sites of disease) should be identified as “non-target” lesions and should 
also be recorded at baseline. Measurements of these lesions are not required but these 
lesions should be followed as ‘present’, ‘absent’ or in rare cases ‘unequivocal progression’ 
and recorded. 
 
Response Criteria 
 
A. Evaluation of Target Lesions 
 
Response Category 
Description 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference the 
baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one or more 
new lesions. In addition to this, the sum must also demonstrate an absolute increase of 
at least 5 mm. The appearance of one or more lesion is also considered progression.  
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started 
 
B. Evaluation of Non-target Lesions 
 
Response Category 
Description 
Complete Response (CR) 
Disappearance of all non-target lesions  
Incomplete Response/ 
Stable Disease (SD) 
Persistence of one or more non-target lesion(s)  
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions 1  
 
Notes: 
1. To achieve “unequivocal progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumour 
burden has increased sufficiently to merit discontinuation of therapy. 
 
 

 
 
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C. Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of treatment until 
disease progression In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
D. Overall Responses for all Possible Combinations of Tumour Responses in Target 
and Non-target Lesions With or Without the Appearance of New Lesions 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response (CR) 
CR 
No 
CR 
Complete response (CR) 
Non-CR/non-PD 
No 
PR 
Complete response (CR) 
Not evaluated 
No 
PR 
Partial response (PR) 
Non-PD 
No 
PR 
Stable disease (SD) 
Non-PD 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable (NE) 
Progressive disease (PD) 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
"symptomatic deterioration." Every effort should be made to document the objective disease 
progression, even after discontinuation of treatment. 
 
Frequency of Tumour Re-evaluations 
 
For the PePS2 trial, clinical response rate, durable clinical benefit (CR+PR+SD≥18 weeks), 
PFS and duration of response will be evaluated radiologically by a CT scan of the chest and 
abdomen and other clinically relevant areas at baseline and at 9 weekly intervals and by 
clinical measurement at 3 weekly intervals until progression or discontinuation of trial 
medication. The final CT scan should be performed within 28 days of discontinuation of trial 
medication. 
For patients who discontinue treatment prior to progression CT scans and clinical 
measurements should, where possible, continue to be performed in accordance with the 
relevant schedule of assessments. 
 
 

 
 
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Appendix 3: Cockcroft and Gault equation 
 
 
Cockcroft and Gault creatinine clearance (CrCl): 
 
 
 
 
 
 
 
 
CrCl (mL/min) = N x [140-age (years)] x weight (kg) 
 
 
Serum creatinine (micromol/L) 
 
 
Where N = 1.23 males, 1.04 females 

 
 
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Appendix 4: Charlson Index 
 
The Charlson Index (30) will be used in this trial for the assessment of comorbiditiy. 
Score 
Condition 
1 
Myocardial infarction (history, not ECG changes only) 
Congestive heart failure 
Peripheral vascular disease (includes aortic aneurysm ≥6cm) 
Cerebrovascular disease: CVA with mild or no residua or TIA 
Dementia 
Chromic pulmonary disease 
Connective tissue disease 
Peptic ulcer disease 
Mild liver disease (without portal hypertension, includes chronic hepatitis) 
Diabetes without end-organ damage (excludes diet-controlled alone) 
2 
Hemiplegia 
Moderate or severe renal disease 
Diabetes with end-organ damage (retinopathy, neuropathy, nephropathy, 
or brittle diabetes) 
Tumour without metastasis (exclude if >5 years from diagnosis) 
Leukemia (acute or chronic) 
Lymphoma 
3 
Moderate or severe liver disease 
6 
Metastatic solid tumour 
AIDS (not just HIV positive) 
NOTE: For each decade >40 years of age, a score of 1 is added to the total score. 
Abbreviations: ECG, electrocardiogram; CVA, cerebrovascular accident; TIA, transient ischemic 
attack; AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus 
 

 
 
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Appendix 5: Quality of Life Questionnaires 
A. Functional Assessment of Cancer Therapy – Lung (FACT-L) 
*as available on www.facit.org 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ......................................
0 
1 
2 
3 
4 
GP2 
I have nausea ....................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family .............
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain .........................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends ....................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ..............
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .....................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication 
about my illness .................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who 
is my main support) ...........................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual 
activity, please answer the following question. 
If you prefer not to answer it, please mark this 
box      and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................
0 
1 
2 
3 
4 

 
 
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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad............................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness ................................................................
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..
0 
1 
2 
3 
4 
GE4 
I feel nervous .....................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse .............
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A 
little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ........
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life.........................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ..............................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .......
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now ...................................................................
0 
1 
2 
3 
4 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
B1 
I have been short of breath ................................
0 
1 
2 
3 
4 
C2 
I am losing weight ..............................................
0 
1 
2 
3 
4 
L1 
My thinking is clear ............................................
0 
1 
2 
3 
4 
L2 
I have been coughing ........................................
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss .................................
0 
1 
2 
3 
4 
C6 
I have a good appetite .......................................
0 
1 
2 
3 
4 
L3 
I feel tightness in my chest ................................
0 
1 
2 
3 
4 
L4 
Breathing is easy for me ....................................
0 
1 
2 
3 
4 
Q3 
Have you ever smoked?  
No ___ Yes ___ If yes: 
L5 
I regret my smoking ...........................................
0 
1 
2 
3 
4 
 
 
 
 

 
 
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B. EQ-5D Questionnaire 
 
As available of www.euroqol.org (31) 
 
C. Patient Generated Subjective Global assessment – Box 4 
 
 
 
Box 4. Activities and Function: Over the past month I would 
generally rate my activity as: 
0- Normal with no limitations 
1- Not my normal self, but able to be up and about with fairly 
normal activities 
2- Not feeling up to most things, but in bed or chair less than 
half the day 
3- Able to do little activity and spend most of the day in bed or 
chair 
4- Pretty much bedridden, rarely out of bed 

 
 
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Appendix 6: Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 
Toxicities will be recorded according to the Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0. The full CTCAE document is available on the National Cancer Institute 
(NCI) website, the following address was correct when this version of the protocol was 
approved: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 

 
 
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Appendix 7: Adverse Event definition 
Adverse Event 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
Comment: 
An AE can therefore be any unfavourable and unintended sign (including abnormal 
laboratory findings), symptom or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal 
product. 
 
Adverse Reaction 
All untoward and unintended responses to an IMP related to any dose administered.  
Comment:  
An AE judged by either the reporting Investigator or Sponsor as having causal relationship to 
the IMP qualifies as an AR. The expression reasonable causal relationship means to convey 
in general that there is evidence or argument to suggest a causal relationship. 
 
Serious Adverse Event  
Any untoward medical occurrence or effect that at any dose:  
• Results in death  
• Is life-threatening* 
• Requires hospitalisation** or prolongation of existing inpatients’ hospitalisation 
• Results in persistent or significant disability or incapacity  
• Is a congenital anomaly/birth defect 
• Or is otherwise considered medically significant by the Investigator*** 
 
Comments:  
The term severe is often used to describe the intensity (severity) of a specific event. This is 
not the same as serious, which is based on patients/event outcome or action criteria. 
* Life threatening in the definition of an SAE refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
**Hospitalisation is defined as an unplanned, formal inpatient admission, even if the 
hospitalisation is a precautionary measure for continued observation. Thus hospitalisation for 
protocol treatment (e.g. line insertion), elective procedures (unless brought forward because 
of worsening symptoms) or for social reasons (e.g. respite care) are not regarded as an SAE. 
*** Medical judgment should be exercised in deciding whether an AE is serious in other 
situations. Important AEs that are not immediately life threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should be considered serious. 
 
Serious Adverse Reaction  
An Adverse Reaction which also meets the definition of a SAE. 
 
Suspected Unexpected Serious Adverse Reaction 
A SAR that is unexpected i.e. the nature, or severity of the event is not consistent with the 
applicable product information. 
A SUSAR should meet the definition of an AR, UAR and SAR. 
 

 
 
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Unexpected Adverse Reaction 
An AR, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator Brochure (IB) for an unapproved IMP or (compendium of) 
Summary of Product Characteristics (SPC) for a licensed product).  
When the outcome of an AR is not consistent with the applicable product information the AR 
should be considered unexpected. 
 
Events of Clinical Interest 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune 
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicated a 
possible immune-related ECI then additional testing should be performed to rule out other 
etiologic causes. If no other cause was found, then it is assumed to be immune-related (ir).  
An irAE is defined as a clinically significant AE of any organ that is associated with study 
drug exposure, is of unknown etiology, and is consistent with an immune -related 
mechanism. It is possible that irAEs other than those listed may be observed in subjects 
receiving pembrolizumab; therefore, all AEs of unknown etiology associated with drug 
exposure should be evaluated to determine if it is possibly immune related. This is meant to 
be a general guidance; therefore, recommendations in the current document might not be all 
inclusive. As such Investigators are encouraged to contact the PePS2 Trial Office as needed 
to discuss cases that warrant separate discussion outside of the scope of current guidelines. 
Permanent discontinuation of pembrolizumab due to irAE may be subject of discussion 
between the Trial Office and treating Investigator. 
The most commonly reported immune-related adverse events across the dose schedules are 
hypothyroidism (7.2%), pneumonitis (2.9%), hyperthyroidism (2.2%), colitis (1.3%) and skin 
AEOSI (1.3% including all terms). Based on the mechanism of action of pembrolizumab and 
similar immunomodulatory agents, MSD is interested in potential irAEs, and encourages 
appropriate investigation of signs and symptoms suggestive of these. Consultation with the 
appropriate medical specialist should be considered when investigating a possible irAE. 
These events can occur after the first dose to several months after the last dose of treatment. 
Mild irAEs are usually treated symptomatically and do not require dosing delays or 
discontinuation. Higher grade and persistent lower grade irAEs typically necessitate 
withholding or discontinuing treatment and administration of systemic steroids or other 
immunosuppressive agents (such as tumor necrosis factor blockers), when systemic steroids 
are not effective. Early recognition of irAEs and initiation of treatment are critical to reduce 
the risk of complications, since the majority of irAEs are reversible with the use of steroids 
and other immune suppressants 
Most immune-related adverse reactions occurring during treatment with pembrolizumab were 
reversible 
and 
managed 
with 
interruptions 
of 
pembrolizumab, 
administration of 
corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred 
after the last dose of pembrolizumab. 
For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology 
or exclude other causes should be ensured. Based on the severity of the adverse reaction, 
pembrolizumab should be withheld and corticosteroids administered. Upon improvement to 
Grade ≤ 1, corticosteroid taper should be initiated and continued over at least 1 month. 
Based on limited data from clinical studies in patients whose immune-related adverse 
reactions could not be controlled with corticosteroid use, administration of other systemic 
immunosuppressants can be considered. 
Pembrolizumab may be restarted within 12 weeks after last dose if the adverse reaction 
remains at Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or 
equivalent per day. 

 
 
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Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse 
reaction that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for 
endocrinopathies that are controlled with replacement hormones. 
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 
PePS2 Trial Office. 
 
 

 
 
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Appendix 8: WMA Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Recommendations guiding physicians in biomedical research involving human 
subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964  
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
and the 
48th General Assembly, Somerset West, Republic of South Africa, October 1996 
 
INTRODUCTION 
It is the mission of the physician to safeguard the health of the people. His or her knowledge 
and conscience are dedicated to the fulfilment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The Health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient." 
 
The purpose of biomedical research involving human subjects must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology 
and pathogenesis of disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.  
 
Because it is essential that the results of laboratory experiments be applied to human beings 
to further scientific knowledge and to help suffering humanity, the World Medical Association 
has prepared the following recommendations as a guide to every physician in biomedical 
research involving human subjects. They should be kept under review in the future. It must 
be stressed that the standards as drafted are only a guide to physicians all over the world. 
Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of 
their own countries. 
 
I. BASIC PRINCIPLES 
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 

 
 
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2. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent of 
the Investigator and the sponsor provided that this independent committee is in 
conformity with the laws and regulations of the country in which the research experiment 
is performed. 
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person 
and never rest on the subject of the research, even though the subject has given his or 
her consent. 
4. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
5. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society. 
6. The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
7. Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable. 
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits. 
8. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time. The physician should then obtain the subject's freely-
given informed consent, preferably in writing. 
10. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship. 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation. Whenever the minor child is in fact able to give consent, the minor's 
consent must be obtained in addition to the consent of the minor's legal guardian. 

 
 
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12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
 (Clinical Research) 
1. In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgement it offers hope of saving life, re-
establishing health or alleviating suffering. 
2. The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
3. In any medical study, every patient - including those of a control group, if any - should be 
assured of the best proven diagnostic and therapeutic method. This does not exclude the 
use of inert placebo in studies where no proven diagnostic or therapeutic method exists. 
4. The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
5. If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2). 
6. The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (Non-Clinical Biomedical Research) 
1. In the purely scientific application of medical research carried out on a human being, it is 
the duty of the physician to remain the protector of the life and health of that person on 
whom biomedical research is being carried out. 
2. The subject should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient's illness. 
3. The Investigator or the investigating team should discontinue the research if in his/her or 
their judgement it may, if continued, be harmful to the individual. 
4. In research on man, the interest of science and society should never take precedence 
over considerations related to the wellbeing of the subject. 
 
 

 
 
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Coordinating Trial Office 
 
PePS2 Trial Office 
Cancer Research UK Clinical Trials Unit 
Institute of Cancer and Genomic Sciences 
University of Birmingham 
B15 2TT 
 
Tel: 0121 414 6788 
Fax: 0121 414 3529 
Email: peps2@trials.bham.ac.uk 
 
 
 
 
Patient Registration 
 
Tel: 0121 414 6788 / 6754 
Monday to Friday, 9:00am to 5:00pm 
 
 
 
 
Serious Adverse Event Reporting 
 
Fax SAE forms to: 
0121 414 3529 or 0121 414 7989