Conditions: Non-muscle Invasive Bladder Cancer (NMIBC)
Keywords: Recurrent intermediate risk NMIBC Intravesical Pembrolizumab Intravenous Pembrolizumab Phase I/II Marker-lesion Non-muscle invasive bladder cancer (NMIBC)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
A parallel group, open label, multi-centre, phase I/II marker-lesion study of intravesical or intravenous pembrolizumab in recurrent intermediate risk NMIBC. Thirty patients (fifteen in each of two arms) will be randomised 1:1 to treatment with either intravesical pembrolizumab (Arm A) or intravenous pembrolizumab (Arm B). The main study will be preceded by a single institution safety run-in phase involving intra-patient dose escalation in six patients to confirm the safety and tolerability of intravesical pembrolizumab and the dose to be used in the randomised phase.

Detailed description:
Bladder cancer is the seventh most common cancer in the United Kingdom (UK) and ninth most common cancer worldwide. New strategies for treating this disease are urgently required to reduce recurrence and progression rates. Pembrolizumab is a type of immunotherapy drug that has been approved for use in certain types of melanoma and lung cancer. It is thought to work by helping the body's immune system to recognise and attack cancer. Drugs that work in a similar way have shown some encouraging results in studies treating patients with bladder cancer that has spread to other parts of the body, although they are not currently approved for treating either advanced or localised bladder cancer.

This trial is being performed to assess the safety and tolerability of giving pembrolizumab to patients with localised bladder cancer and to study what effects the drug has on the tumour; Participants will have all but one tumour (referred to as the marker lesion) removed during their transurethral resection of bladder tumour (TURBT) procedure at the start of the trial. After trial treatment, a further TURBT procedure will be carried out to remove the marker lesion, or if the marker lesion is no longer visible, a biopsy will be taken of the area where the growth was before.

After a safety run in with intra-patient dose escalation of intravesical pembrolizumab performed in paired patient cohorts, the trial will test two different ways of giving the pembrolizumab; directly into the bladder (intravesical) with 6 doses being received over 6 weeks and with a further dose approximately 3 weeks later, or into the blood stream via the veins (intravenous) with a dose being received every 3 weeks for a maximum of 4 doses.

36 eligible participants from across 3 UK centres will be randomly allocated to receive treatment by one of these ways. Following the end of treatment visit, patients will return to receiving standard care but receive follow-up for up to 2 years.

Arms:
arm 1: Intravesical Pembrolizumab (solution for infusion) 50-200 mg, given on D1, D8, D15, D22, D29, D36 \& D64.

Dose to be decided after safety run-in. arm 2: Intravenous Pembrolizumab (solution for infusion), 200mg, given on D1, D22, D43, D64

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Solution for Infusion (Intravesical and Intravenous) 100mg/ 4ml vial

Protocol document:
Prot_000.pdf: 
                              
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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
 
 
 
 
 
Full title: A parallel group phase I/II marker lesion study to assess the safety, 
tolerability and efficacy of intravenous or intravesical pembrolizumab in 
intermediate risk recurrent non-muscle invasive bladder cancer 
Short title:  PemBla - Pembrolizumab in intermediate risk recurrent non-muscle 
invasive bladder cancer (NMIBC). 
 
 
 
 
Protocol Version & date: 
V3.0 08Mar2018 
Protocol Number: 
OCTO-089 
EudraCT Number: 
2016-002267-33 
IRAS Project ID: 
209428 
REC Reference: 
17/SC/0121 
ClinicalTrials.gov Identifier: 
NCT03167151 
 
 
 
Sponsor:  
University of Oxford 
Funder:  
Merck Sharp & Dohme 
Conflict of Interest statement 
None of the protocol authors have declared a potential 
conflict of interest 
  
Confidentiality Statement 
This document contains confidential information that must 
not be disclosed to anyone other than the Sponsor, the Trial 
Office, the Investigator Team, host NHS Trust(s), regulatory 
authorities, and members of the Research Ethics Committee 
unless authorised to do so.   
 
 
 
 


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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
Key trial contacts 
 
Chief Investigator 
 
 
 
 
 
 
 
 
 
Clinical Lead 
Responsible Investigator (under regulatory requirements): 
Prof Andrew Protheroe 
Department of Oncology 
Oxford Cancer and Haematology Centre 
Churchill Hospital 
Oxford University Hospitals NHS Trust 
Old Road, Oxford.  OX3 7LJ 
Tel: +44 (0)1865 572300 
Email: andrew.protheroe@oncology.ox.ac.uk  
 
Mr Jeremy Crew 
 
Department of Urology 
Churchill Hospital 
Oxford University Hospitals NHS Trust 
Old Road, Oxford.  OX3 7JU 
 
Tel: +44 (0)1865 227063  
 
 
Academic Lead 
Email: jeremy.crew@ouh.nhs.uk  
 
Prof Vincenzo Cerundolo 
MRC Human Immunology Unit 
Weatherall Institute of Molecular Medicine 
Oxford, OX3 9DS 
Tel: +44 (0)1865 222412 
Email: vincenzo.cerundolo@imm.ox.ac.uk     
 
 
Clinical Research Fellow 
 
 
 
 
 
 
 
 
 
Dr Victoria Woodcock 
Early Phase Clinical Trials Unit 
Department of Oncology 
Churchill Hospital 
Old Road, Oxford.  OX3 7JE. 
Tel: +44(0)1865 235469 
Email: victoria.woodcock@oncology.ox.ac.uk  
Oxford Clinical Trial Office (OCTO) 
PemBla Trial Office 
 
Oncology Clinical Trials Office (OCTO) 
 
Department of Oncology, The University of Oxford 
 
Old Road Campus Research Building 
 
Oxford OX3 7DQ, UK 
 
Tel: +44 (0)1865 227190  
 
Email: octo-pembla@oncology.ox.ac.uk  
 
Website: http://www.oncology.ox.ac.uk/trial/pembla 
 
 
Sponsor 
The University of Oxford 
Ms Heather House 
Clinical Trials & Research Governance 
Joint Research Office 
Block 60, Churchill Hospital, Headington 
Oxford, OX3 7LE, UK 
Email: ctrg@admin.ox.ac.uk  
 
Statistician 
Ms Sharon Love 
Senior Medical Statistician 


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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford.  OX3 7LD 
 
Tel: +44 (0)1865 223441 
 
Email: sharon.love@csm.ox.ac.uk    
 
Dr Joanna Moschandreas 
Senior Medical Statistician 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford.  OX3 7LD 
Email:  joanna.moschandreas@csm.ox.ac.uk  
 
 
Clinical queries and emergency contact details 
 
During office hours: Clinical Queries should be directed to the PEMBLA Trial Office and contact the Clinical Trial 
Coordinator.  The call will be passed on to the Chief Investigator or to the Clinical Coordinator (medically qualified) or 
an appropriate member of the Trial Management Group. 
 
Out of office hours: call the Oxford University Hospitals NHS Foundation Trust switchboard on Tel: 0300 304 7777 and 
ask to bleep the PEMBLA Clinical Trial Clinician. 
 
Patient Registration/Randomisation: See section 4.5. 
 
Protocol Authors and Affiliations: 
 
Jeremy Crew 
Consultant Urologist 
Department of Urology, Oxford University 
Hospitals NHS Trust 
 
 
 
Vincenzo Cerundolo 
Professor of Immunology 
MRC Human Immunology Unit, Weatherall 
Institute of Molecular Medicine, University of 
Oxford 
 
 
 
Andrew Protheroe 
Consultant in Medical Oncology 
Department of Oncology, Oxford University 
Hospitals NHS Trust 
 
 
 
Mark Middleton 
Professor of Experimental Cancer Medicine 
University of Oxford Department of Oncology, 
Churchill Hospital, Oxford 
 
 
 
Victoria Woodcock 
Clinical Research Fellow 
Early Phase Clinical Trials Unit, Churchill 
Hospital, Oxford 
 
 
 
Giorgio Napolitani 
Senior Postdoctoral Fellow 
MRC Human Immunology Unit, Weatherall 
Institute of Molecular Medicine, University of 
Oxford 
 
 
 
Mariolina Salio 
Clinical Research Fellow 
MRC Human Immunology Unit, Weatherall 
Institute of Molecular Medicine, University of 
Oxford 
 
 
 


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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
Sharon Love 
 
 
Joanna 
Moschandreas 
Senior Medical Statistician 
 
 
Senior Medical Statistician 
Oxford Clinical Trials Research Unit, University 
of Oxford 
 
Oxford Clinical Trials Research Unit, University 
of Oxford 
 
 
 
Linda Collins 
 
 
Claire Scudder 
Portfolio Lead, Early Phase Medical 
Oncology 
 
Portfolio Lead 
Oncology Clinical Trials Office, University of 
Oxford 
 
Oncology Clinical Trials Office, University of 
Oxford 
 
Lucy Griffiths 
 
 
Chrissie Butcher 
Trial Manager, Early Phase Medical 
Oncology 
 
Trial Manager, Early Phase Medical 
Oncology 
 
Oncology Clinical Trials Office, University of 
Oxford 
 
Oncology Clinical Trials Office, University of 
Oxford 
 
 
 
 
 


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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................................................. 8 
SUMMARY SCHEDULE OF EVENTS .................................................................................................................................. 9 
ABBREVIATIONS ....................................................................................................................................................... 10 
1 
INTRODUCTION ..................................................................................................................................... 11 
1.1 
BACKGROUND .................................................................................................................................................... 11 
1.2 
RATIONALE FOR THE STUDY ................................................................................................................................... 11 
1.3 
INVESTIGATIONAL MEDICINAL PRODUCT(S) USED IN THE STUDY ................................................................................... 12 
1.4 
OTHER RESEARCH INTERVENTIONS .......................................................................................................................... 13 
2 
TRIAL DESIGN......................................................................................................................................... 13 
2.1 
DURATION OF PATIENT PARTICIPATION .................................................................................................................... 15 
2.2 
POST-TRIAL CARE AND FOLLOW-UP......................................................................................................................... 15 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 15 
4 
PATIENT SELECTION ............................................................................................................................... 16 
4.1 
ELIGIBILITY CRITERIA ............................................................................................................................................ 16 
4.2 
EXCLUSION CRITERIA: .......................................................................................................................................... 17 
4.3 
PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA........................................................................................... 18 
4.4 
RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME ROUND ......................................... 18 
4.5 
PATIENT REGISTRATION AND RANDOMISATION PROCEDURE ......................................................................................... 18 
4.5.3 
SAFETY RUN IN PHASE .......................................................................................................................................... 19 
5 
TRIAL ASSESSMENTS AND PROCEDURES ................................................................................................ 19 
5.1 
INFORMED CONSENT ........................................................................................................................................... 19 
5.2 
SCREENING EVALUATIONS ..................................................................................................................................... 21 
5.3 
EVALUATIONS DURING THE STUDY .......................................................................................................................... 21 
5.4 
END OF STUDY/TREATMENT EVALUATIONS ............................................................................................................... 24 
5.5 
EVALUATIONS ON EARLY WITHDRAWAL ................................................................................................................... 25 
6 
EARLY PATIENT WITHDRAWAL .............................................................................................................. 25 
6.1 
PATIENT EVALUABILITY AND REPLACEMENT .............................................................................................................. 26 
7 
SAMPLES FOR LABORATORY ANALYSIS .................................................................................................. 26 
7.1 
SAMPLES TO BE ANALYSED IN LOCAL TRUST’S LABORATORIES ....................................................................................... 26 
7.2 
SAMPLES TO BE SENT TO AND ANALYSED IN CENTRAL ANALYTICAL LABORATORIES ............................................................ 26 
 
FORMALIN FIXED PARAFFIN EMBEDDED (FFPE) TUMOUR SAMPLE FOR PD-L1 EXPRESSION ANALYSIS (5 UNSTAINED SLIDES) 
TUMOUR SAMPL ................................................................................................................................................ 26 
7.3 
PHARMACODYNAMIC AND TRANSLATIONAL ASSAYS ................................................................................................... 26 
7.4 
SUMMARY OF SAMPLES/ASSAYS TO BE TAKEN DURING THE STUDY ................................................................................ 27 
7.5 
LABELLING AND CONFIDENTIALITY OF SAMPLES SENT .................................................................................................. 27 
7.6 
CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS................................................................................. 27 
7.7 
SAMPLES FOR BIOBANKING ................................................................................................................................... 27 
7.8 
TRIAL SAMPLE CUSTODIANSHIP AND RETENTION AT END OF STUDY ................................................................................ 27 
7.9 
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION .................................................................... 27 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) ................................................................................. 27 
8.1 
NAME OF IMPS ................................................................................................................................................. 27 
8.2 
TREATMENT DOSE AND DURATION ......................................................................................................................... 28 
8.3 
MANAGEMENT OF DRUG ADMINISTRATION .............................................................................................................. 28 
8.4 
SPECIAL PRECAUTIONS ......................................................................................................................................... 29 
8.5 
DOSE MODIFICATION ........................................................................................................................................... 29 
8.6 
MANAGEMENT OF OVERDOSE ............................................................................................................................... 32 


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CANCER (NMIBC) 
9 
OTHER TREATMENTS (NON-IMPS) ......................................................................................................... 32 
9.1 
SUPPORT MEDICATION ......................................................................................................................................... 32 
9.2 
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ........................................................................................... 35 
9.3 
PROHIBITED THERAPIES ........................................................................................................................................ 35 
9.4 
DRUG INTERACTIONS ........................................................................................................................................... 35 
10 
DRUG MANAGEMENT ............................................................................................................................ 35 
10.1 
DRUG SUPPLIES .................................................................................................................................................. 35 
10.2 
DRUG ORDERING ................................................................................................................................................ 36 
10.3 
IMP RECEIPT ..................................................................................................................................................... 36 
10.4 
HANDLING AND STORAGE ..................................................................................................................................... 36 
10.5 
DOSING DISPENSING ............................................................................................................................................ 36 
10.6 
DRUG ACCOUNTABILITY........................................................................................................................................ 36 
10.7 
DRUG DESTRUCTION ............................................................................................................................................ 36 
10.8 
OCCUPATIONAL SAFETY ........................................................................................................................................ 37 
10.9 
PRODUCT QUALITY COMPLAINTS: ........................................................................................................................... 37 
11 
EVALUATION OF RESPONSE` .................................................................................................................. 37 
11.1 
TUMOUR ASSESSMENT ......................................................................................................................................... 37 
11.2 
TUMOUR RESPONSE ............................................................................................................................................ 37 
11.3 
OTHER DEFINITIONS OF OUTCOME: ........................................................................................................................ 38 
12 
SAFETY REPORTING ............................................................................................................................... 38 
12.1 
ADVERSE EVENT DEFINITIONS ............................................................................................................................... 38 
12.2 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ...................................... 39 
12.3 
DETERMINING ADVERSE EVENT CAUSALITY ............................................................................................................... 39 
12.4 
REFERENCE SAFETY INFORMATION (RSI) FOR ASSESSMENT OF EXPECTEDNESS ................................................................. 40 
12.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) .................................................................... 40 
12.6 
EXPEDITED REPORTING OF SAES ............................................................................................................................ 40 
12.7 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS .............................................................................................................. 41 
12.8 
REPORTING ADVERSE EVENTS ON THE CRF .............................................................................................................. 41 
12.9 
EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAES............................................................................................... 42 
12.10 
INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ........................................................................................ 42 
13 
PREGNANCY ........................................................................................................................................... 42 
14 
DEFINING THE END OF TRIAL ................................................................................................................. 43 
15 
STATISTICAL CONSIDERATIONS .............................................................................................................. 43 
15.1 
SAMPLE SIZE AND POWER ..................................................................................................................................... 43 
16 
STATISTICAL ANALYSIS PLAN ................................................................................................................. 43 
16.1 
INCLUSION IN ANALYSIS ........................................................................................................................................ 44 
16.2 
SUBGROUP ANALYSIS ........................................................................................................................................... 44 
16.3 
INTERIM ANALYSES ............................................................................................................................................. 44 
16.4 
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN .................................................. 44 
16.5 
FINAL ANALYSIS .................................................................................................................................................. 44 
17 
TRIAL COMMITTEES ............................................................................................................................... 44 
17.1 
TRIAL MANAGEMENT GROUP (TMG) .................................................................................................................... 44 
17.2 
DATA AND SAFETY MONITORING ........................................................................................................................... 44 
17.3 
TRIAL STEERING COMMITTEE ................................................................................................................................ 44 
18 
DATA MANAGEMENT ............................................................................................................................ 44 
18.1 
DATABASE CONSIDERATIONS ................................................................................................................................. 44 
18.2 
CASE REPORTS FORMS (CRFS) ............................................................................................................................... 44 
18.3 
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .......................................................................................... 45 


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19 
CLINICAL STUDY REPORT ....................................................................................................................... 45 
20 
STUDY SITE MANAGEMENT ................................................................................................................... 45 
20.1 
STUDY SITE RESPONSIBILITIES ................................................................................................................................ 45 
20.2 
STUDY SITE SET UP AND ACTIVATION ....................................................................................................................... 45 
20.3 
STUDY DOCUMENTATION ..................................................................................................................................... 45 
21 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 46 
21.1 
ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL ............................................................................................. 46 
21.2 
REGULATORY AUTHORITY APPROVAL ...................................................................................................................... 46 
21.3 
NHS RESEARCH GOVERNANCE .............................................................................................................................. 46 
21.4 
PROTOCOL AMENDMENTS .................................................................................................................................... 46 
21.5 
URGENT SAFETY MEASURES .................................................................................................................................. 46 
21.6 
TEMPORARY HALT ............................................................................................................................................... 47 
21.7 
SERIOUS BREACHES ............................................................................................................................................. 47 
21.8 
TRIAL REPORTS .................................................................................................................................................. 47 
22 
EXPENSES AND BENEFITS ....................................................................................................................... 47 
23 
QUALITY ASSURANCE ............................................................................................................................ 47 
23.1 
RISK ASSESSMENT ............................................................................................................................................... 47 
23.2 
MONITORING .................................................................................................................................................... 48 
23.3 
AUDIT AND REGULATORY INSPECTION ..................................................................................................................... 48 
24 
RECORDS RETENTION & ARCHIVING ...................................................................................................... 48 
25 
PATIENT CONFIDENTIALITY .................................................................................................................... 48 
26 
STUDY FUNDING .................................................................................................................................... 49 
27 
SPONSORSHIP AND INDEMNITY ............................................................................................................ 49 
27.1 
SPONSORSHIP .................................................................................................................................................... 49 
27.2 
INDEMNITY ........................................................................................................................................................ 49 
27.3 
CONTRACTS/AGREEMENTS ................................................................................................................................... 49 
28 
PUBLICATION POLICY ............................................................................................................................. 49 
29 
REFERENCES ........................................................................................................................................... 49 
APPENDIX 1: ECOG PERFORMANCE SCALE ................................................................................................................ 51 
APPENDIX 2: EAU RISK CATEGORIES ......................................................................................................................... 52 
APPENDIX 3: EORTC RISK TABLES .............................................................................................................................. 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
PROTOCOL SYNOPSIS 
 
Full Title of study: 
A parallel group phase I/II marker lesion study to assess the safety, tolerability and 
efficacy of intravenous or intravesical pembrolizumab in intermediate risk recurrent 
non-muscle invasive bladder cancer 
Short Title: 
Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer 
(NMIBC) 
Trial Acronym: 
PemBla 
Clinical Phase: 
Phase I/II 
Study Design: 
A parallel group, open label, multi-centre, randomised, phase I/II marker-lesion study of 
intravesical or intravenous pembrolizumab.  The main study will be preceded by a safety 
run-in with intra-patient dose escalation of intravesical pembrolizumab performed in 
paired patient cohorts to confirm the safety and tolerability of intravesical 
pembrolizumab and the dose to be used in the randomised phase.    
 
Objectives 
Endpoints 
Primary: 
To assess the safety, tolerability and 
toxicities of intravesical and intravenous 
pembrolizumab after TURBT in patients 
with intermediate risk NMIBC  
Incidence and severity of adverse events 
(NCI CTCAE v4.03) 
Secondary: 
To provide a preliminary assessment of 
efficacy of treatment with intravesical 
pembrolizumab in patients with 
intermediate risk NMIBC  
 Complete response rate of marker-
lesion as assessed clinically at TURBT 
and confirmed on biopsy of tumour 
bed 
 Recurrence and progression-free 
intervals  
 
To provide a preliminary assessment of 
efficacy of treatment with intravenous 
pembrolizumab in patients with 
intermediate risk NMIBC 
 Complete response rate of marker-
lesion as assessed clinically at TURBT 
and confirmed on biopsy of tumour 
bed 
 Recurrence and progression-free 
intervals  
Tertiary: 
Refer to Section 3 Objectives and Endpoints for the list of Tertiary objectives and 
endpoints 
Planned enrolment: 
Six patients will be enrolled in the safety-run in of intravesical pembrolizumab 
Thirty patients (fifteen in each of two arms) will be randomised 1:1 to treatment with 
either intravesical pembrolizumab (Arm A) or intravenous pembrolizumab (Arm B).   
Target Population: 
Patients with recurrent intermediate risk NMIBC 
Investigational 
Medicinal Product(s) 
Pembrolizumab   Solution for infusion, 200mg, intravenous 
Pembrolizumab   Solution for infusion, 50-200mg, intravesical                       
Treatment Duration 
Participants in the main study will be in the study for approximately 15 weeks from the 
time of first TURBT to the end of treatment visit.  Participants in the safety-run in period 
will be in the study for approximately 11 weeks from the time of their TURBT to the end 
of treatment visit. 
Follow-up duration 
Following the end of treatment visit, patients will receive standard care.  Patients in the 
main study will be followed up via the medical care team for 2 years or until disease 
recurrence, progression or death whichever is sooner. 
End of study 
Last Patient Last Visit, and up to 24 months for follow-up. 
 


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CANCER (NMIBC) 
SUMMARY SCHEDULE OF EVENTS 
Visit Description 
Screening 
TURBT 
Pre-treatment 
On treatment 
TURBT 
End of 
treatment visit 
Follow-up 
Day 
-44 to 
-15 
-14 
-13 
to 1 
1 
 
8 
 
15 
 
22 
 
29 
 
36 
 
43 
 
50 
 
64 
 
85 
+/-7 
92§ 
+7 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Physical examination 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Vital signsa 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Blood for haem and biochemb 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Blood for TFTsc 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
Urinalysisd 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Pregnancy test 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Blood for germline DNAe 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood for immunoprofilingf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X+ 
X 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resection of bladder tumour(s) 
TURBT 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Tumour assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
Bladder barbotage 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Bladder biopsyg 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Urine for cytokinesh 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Research Blood **i  
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Administration of intravesical 
Pembrolizumab (Safety run-in 
and Arm A) j 
 
 
 
X 
 
X 
+/-1 
X 
+/-1 
X 
+/-1 
X 
+/-1 
X 
+/-1 
 
 
X* 
+/-1 
 
 
 
Administration of intravenous 
Pembrolizumab (Arm B) j 
 
 
 
X 
 
 
X 
+/-3 
 
 
X 
+/-3 
 
X 
+/-3 
 
 
 
Recurrence data (RFI and PFI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Optional  tumour sample at 
recurrence or progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Visits shaded in grey are only applicable to patients who are due for drug administration on that day 
* For patients in the main study only (not patients in safety-run in) 
** For patients receiving intravesical treatment only 
+ For patients who have consented to having second non-marker lesions resected only 
§ The end of study visit for patients in the safety run-in will be performed on day 64 
a Vital signs to include systolic / diastolic blood pressure, pulse rate, respiratory rate, oxygen saturations and temperature.  To be 
performed according to the vital signs scheduling details in section 8.3. 
b To include FBC, clotting screen, sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, ALP, 
AST and/or ALT 
c To include TSH, T3 and T4 
d To include Blood, White Cells, Protein, Nitrites, pH, culture and sensitivity 
e 10ml of blood in EDTA tube, taken pre-treatment 
f 50ml of blood in Na-Heparin tubes 
g Biopsy of normal bladder epithelium + tumour bed if complete response of marker lesion 
h For patients receiving intravesical treatment, urine for cytokines will be collected pre-dose and post-dose (first post-treatment 
urine sample after the drug has been voided from the bladder) on day 1 and thereafter post-dose only.  For patients receiving 
intravenous treatment, urine for cytokines will be collected pre-dose only.  
i Blood for research will be taken pre-dose and 2 hours post dose (counted from the completion of syringe/catheter administration 
of suspension into the bladder) for patients receiving intravesical treatments on day 1, and pre-dose only at cycle 6 (d36).  
j Trial treatment should begin 14 days after TURBT or as close as possible to this date. 


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CANCER (NMIBC) 
ABBREVIATIONS 
ADR 
AE 
Adverse Drug Reaction 
Adverse Event 
BCG 
Bacillus Calmette-Guerin 
CIS 
Carcinoma in situ 
CR 
CRF 
CTA 
DKA 
Complete response 
Case Report Form 
Clinical Trials Authorisation 
Diabetic Ketoacidosis 
DLT 
Dose limiting toxicity 
EAU 
ECG 
ECI 
European Association of Urologists 
Echocardiogram 
Event of Clinical Interest 
EORTC 
European Organisation for Research and Treatment of Cancer 
FACS 
Fluorescence-activated cell sorting 
FFPE 
HRA 
HTA 
Formalin-fixed, paraffin-embedded 
Health Research Authority  
Human Tissue Act 
IB 
IEPTOC 
Investigator Brochure 
Independent Early Phase Trial Oversight Committee 
IMP 
Investigational Medicinal Product 
NMIBC 
Non-muscle invasive bladder cancer 
MMC 
Mitomycin C 
MA 
MSD 
Marketing Authorisation 
Merck & Co., Inc 
MTD 
Maximum tolerated dose 
PBMC 
PD 
Peripheral blood mononuclear cells 
Pharmacodynamics 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PI 
Principal Investigator 
PFI 
REC 
Progression-free Interval 
Research Ethics Committee 
RFI 
Recurrence-free interval 
RSI 
SAE 
Reference safety information  
Serious Adverse Event 
SAR 
SOP 
Serious Adverse Reaction 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
LPLV 
Last visit of the last patient undergoing the trial 
SUSAR 
Suspected Unexpected Serious Adverse Drug Reaction 
TCR 
T cell receptor 
TFT 
Thyroid function test 
TMG 
Trial management group 
TURBT 
Transurethral resection of bladder tumour 
ULN 
Upper limit of normal 
 
 
 
 
 
 
 
 


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CANCER (NMIBC) 
1 
INTRODUCTION 
1.1 
Background  
Bladder cancer is the seventh most common cancer in the UK and ninth most common cancer worldwide with 
429,800 new cases diagnosed in 2012 1.  Urothelial (transitional cell) carcinoma is the predominant histological 
subtype in Europe and the USA where it accounts for 90% of bladder cancers.  In the UK in 2011, there were 10,399 
people diagnosed with bladder cancer and 5,081 deaths from the disease 1.  It is 2–3 times more common in men than 
in women and the incidence is strongly related to age with 50% of cases occurring in people aged over 75 and 90% of 
cases occurring in people aged over 60.  Approximately 70% of patients present with non-muscle invasive bladder 
cancer (NMIBC) that is confined to the mucosa (stage Ta or carcinoma in situ [CIS]) or submucosa (stage T1) 2.   
 
Initial treatment of NMIBC consists of transurethral resection of the bladder tumour (TURBT).  Without additional 
therapy, between 40-80% of tumours will recur within 6-12 months following TURBT and 10-25% will develop muscle 
invasive, regional or metastatic disease 3.  Instillation of a single dose of intravesical chemotherapy at the time of 
TURBT has been shown in meta-analyses to significantly reduce recurrence rates 4 and in practice mitomycin C (MMC) 
is commonly used. Subsequent management is guided by risk stratification based on the pathology results of the 
resected tumour. Patients can broadly be grouped into low, intermediate or high-risk according to the European 
Association of Urologists (EAU) 2013 guidelines 5 (Appendix 2), with individual risks of recurrence and progression 
being established using tables developed by EORTC 6 (Appendix 3).  Further instillation of chemotherapy or 
immunotherapy (typically BCG) into the bladder may be performed for patients at intermediate or high risk.   
 
Despite adjuvant treatment, bladder cancer has a propensity to recur and repeated resection of recurrences and 
further intravesical chemotherapy or immunotherapy, or in some cases cystectomy, may be required.  As such, this 
has significant cost and quality of life implications but yet management of the disease has not significantly changed for 
over 20 years.  New strategies for treating this disease are therefore urgently required to reduce recurrence and 
progression rates. Administration of intravesical BCG was first used in the treatment of bladder cancer in 1976 7 and 
still forms the mainstay of  adjuvant treatment for NMIBC.  Although the exact mechanism of effect is not certain, it is 
generally accepted that it activates non-specific local immunity facilitating recruitment of activated T cells.  Infiltration 
of the bladder with inflammatory cells is seen following treatment 8 accompanied by a significant urinary secretion of 
cytokines 9.  Whilst intravesical BCG has been shown to delay tumour progression 10 , improve overall survival 11 and 
reduce tumour recurrence 12, failure rates of BCG treatment are up to 40% 13.  In addition it is associated with 
significant local and systemic side-effects and approximately 20% of patients discontinue treatment due to this 13.  
Newer immunotherapeutic agents therefore provide a potentially attractive approach to the management of bladder 
cancer.  This trial will evaluate the safety and efficacy of intravenous and intravesical administration of 
Pembrolizumab, a PD-1 inhibitor, in the setting of recurrent intermediate risk bladder cancer. 
1.2 
Rationale for the study 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has long been 
recognised 14.  Bladder tumours are known to possess tumour specific antigens 15 and have high rates of somatic 
mutation 16, potentially increasing the number of antigens that can be identified by the immune system as foreign.  
Accumulating evidence shows a correlation between tumour-infiltrating lymphocytes (TILs) in cancer tissue and 
favourable prognosis in various malignancies including bladder cancer 17 18 19.  In particular, high intratumoural CD8 T 
cell density in urothelial cancers has been associated with better overall and disease specific survival 20 21.   
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress immune control.  The 
normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-
modulate unwanted or excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signalling upon engagement of its ligands (PD-L1 and/or PD-L2) 22.  PD-1 is expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T cells, B-cells, Natural Killer cells, activated monocytes and 
dendritic cells. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
Whilst normal human tissues express little PD-L1, a variety of cancers have been shown to express abundant levels of 
this T-cell inhibitor 23.  Evidence to suggest that the PD-1/PD-L1 pathway may play a critical role in tumour immune 
evasion has led this to being evaluated as a target for therapeutic intervention in a number of cancers. 


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CANCER (NMIBC) 
Pre-clinical  
Studies performed in a range of preclinical models have consistently shown the importance of the PD-1 and PD-L1 
interaction and potential anti-tumour effects that can be achieved by blocking this interaction.  In mouse models, 
expression of PD-L1 rendered tumour cells less susceptible to the effects of cytotoxic T cells in vitro and enhanced 
their invasiveness in vivo, effects that were reversed by anti-PD-L1 Ab 24.  In PD-1 deficient mice, haematogenous 
spread of melanoma cells was inhibited by PD-1 blockade by enhancing infiltration of tumour-specific T cells and 
augmenting cytotoxicity 25.  Substantial anti-tumour effects were also shown in vivo in a murine pancreatic cancer 
model, with PD-L1 blockade promoting CD8+ T cell infiltration into the tumour and inducing local immune activation 
26.  In human models, PD-1/PD-L1 blockade has been shown to increase numbers of cytotoxic T lymphocytes in the 
tumour 27,  and enhance cytolytic activity of tumour specific cytotoxic T lymphocytes 28. 
Clinical 
Targeting the PD-1/PD-L1 pathway has delivered impressive results in trials in a number of malignancies, most notably 
melanoma and is now becoming an accepted treatment approach.  In an early phase study of 135 patients with 
advanced melanoma, anti-PD1 treatment produced an overall response rate of 38%, with many of the responses 
being durable 29.  Further studies in melanoma have produced similar results 30 and trials in non-small cell lung cancer 
31 32, renal cell cancer 33 and head and neck cancer 34 have also shown good responses.  Initial studies of PD-L1 
inhibition in metastatic urothelial cancer have also shown promising results.  In a recent Phase I study 35 patients 
received MPDL3280A, an anti PD-L1 antibody, at a dose of 15 mg/kg intravenously every three weeks for up to a year. 
MPDL3280A was demonstrated to be well tolerated in this pre-treated population with 54% of the patients treated 
responding to treatment. However, since only 20% of bladder cancers appear to express PD-L1 20, treatment with anti-
PD-1 antibodies may be effective in a larger proportion of patients, by targeting the interaction of PD-1 with both PD-
L1 and PD-L2.  Injection of the anti-PD-1 antibody, Pembrolizumab (10 mg/kg intravenously every two weeks), in a 
population of 33 previously treated urothelial patients gave an overall response of 24%, with acceptable safety and 
tolerability profile 36.  Fatigue, rash and diarrhoea were the most common drug-related AEs seen and were mostly 
grade 1-2. 
 
Whilst systemic treatment has not historically been used for treatment of NMIBC due to the limited duration of 
cytotoxic action of chemotherapy agents and associated toxicity, the potentially durable anti-tumour response 
generated by anti-PD1 treatments and acceptable toxicity profile creates the possibility for new systemic approaches 
to treatment that warrant further investigation.  In addition, targeted administration via intravesical injection could 
potentially improve delivery of anti-PD-1 to the tumour site, leading to better clinical responses while reducing toxicity 
due to systemic administration.  Previous studies of intravesical injection of radiolabelled antibodies directed against 
tumour-associated antigens have successfully showed retention of antibodies within the tumour mass 37, suggesting 
that this route of delivery is feasible.  This study will therefore assess both intravenous and intravesical anti-PD1 
antibody treatment in the setting of recurrent NMIBC.  The safety of this treatment strategy will be evaluated and a 
marker lesion approach, described in section 1.4, used to provide an indication of activity.  Should response rates 
meet predefined criteria, larger phase II trials would be developed to further assess the utility of this treatment 
strategy in NMIBC.  
1.3 
Investigational Medicinal Product(s) used in the study  
Pembrolizumab (previously known as MK-3475) is licensed both in the US and EU at a dose of 2mg/kg every three 
weeks for the treatment of patients with unresectable or metastatic melanoma.  It is a potent and highly selective 
humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. 
Pembrolizumab also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma 
(IFNγ), and other cytokines. The antibody potentiates existing immune responses only in the presence of antigen and 
does not nonspecifically activate T-cells. 
 
Various trials have evaluated the safety and clinical efficacy of Pembrolizumab at doses ranging from 1mg/kg to 
10mg/kg and administration schedules of every 2 weeks (Q2W) and every 3 weeks (Q3W).  No maximum tolerated 
dose (MTD) has been identified to date and there is evidence of target engagement and objective evidence of tumour 
size reduction at all dose levels with no clear dose response relationship.  Pharmacodynamic data (IL-2 release assay) 
suggest that peripheral target engagement is durable (>21 days) and pharmacokinetic data analyses show slow 
systemic clearance, limited volume of distribution and a long half-life (26 days).   
 
Choice of dose  


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Based on pharmacokinetic analysis from previous studies, for the intravenous arm of the study we will utilise a fixed 
dose regimen of 200mg Q3W.  This has been shown to provide exposures that are consistent with those obtained with 
a 2mg/kg dose Q3W, which will maintain individual patient exposures in the range established in melanoma as being 
efficacious whilst also being well tolerated and safe.  In addition, utilising a fixed dose regimen will be more 
convenient for physicians and reduce the potential for dosing errors and wastage.   
 
For the intravesical component of the study we will utilise a once weekly dosing schedule over a period of 6 weeks, as 
is convention for intravesical therapy.  A further maintenance intravesical injection will be given on day 64.  Systemic 
absorption of drugs from the bladder is related to a number of factors with a molecular weight below 300kDa being 
one major determinant38.  The approximate molecular weight of Pembrolizumab is 149kDa.  As such, a maximum 
intravesical dose of 200mg will be used to ensure acceptable tolerability should systemic absorption occur. Should the 
entire dose be systemically absorbed, when administered once weekly the cumulative dose will remain below the 
10mg/kg level that has previous been shown to be tolerated when given intravenously on a Q2W schedule.   
1.4 
Other research interventions  
Marker lesion studies 
In an effort to develop new, more effective treatments for NMIBC, a number of novel agents have been trialed using 
marker-lesion studies.  In these studies, a single bladder tumour is left unresected whilst the patient receives further 
intravesical treatment.  The bladder is then re-assessed after an interval of time for response of the marker lesion to 
the treatment, with completion TURBT at that time if the marker lesion persists.  By identifying agents that have the 
ability to eliminate macroscopic disease, drugs that have the potential to eradicate subclinical microscopic disease 
that is likely to contribute to recurrent disease can be identified for further evaluation.  Using a marker-lesion 
approach enables much more rapid evaluation of agents in a substantially smaller number of patients than would be 
required to obtain this information from an adjuvant study.  The CR rate seen in most marker lesion studies is 
between 30-50% and it has been shown that primary tumours have a better CR rate (67%) than recurrent tumours 
(37%) and untreated tumours respond better than those that are pretreated (55% compared with 31% respectively) 
39. 
Studies using marker lesions including over 1200 patients have been shown to be safe with progression to T2 disease 
seen in only 7 patients (0.6%), all of whom had high-risk (G3) tumours 39.  No cases of progression have been seen 
where patients with only intermediate-risk disease have been recruited.  As such, patients who are appropriate for 
marker-lesion studies are those with multiple recurrent intermediate-risk bladder tumours.  Given the lack of 
evidence for the optimum management strategy for these patients, they may potentially benefit from participation in 
such studies without significantly increased risk.  Patients with recurrent high-risk disease may consider radical 
cystectomy or should undergo repeat TURBT and best available therapy and should therefore not be considered.   
 
Most agents assessed in marker lesion studies have shown low toxicity profiles with mild irritative urinary symptoms 
being the most common complaint occurring in up to half of the patients 39.  Given the utility and safety of marker-
lesion studies for the assessment of intravesical agents, extrapolation of this approach to the assessment of systemic 
treatments represents a novel but logical progression.  
 
2 
TRIAL DESIGN 
This is a parallel group, open label, multi-centre, phase I/II marker-lesion study in recurrent intermediate risk NMIBC.  
Thirty patients (fifteen in each of two arms) will be randomised 1:1 to treatment with either intravesical 
pembrolizumab (Arm A) or intravenous pembrolizumab (Arm B).  The main study will be preceded by a safety run-in 
phase involving intra-patient dose escalation in six patients to confirm the safety and tolerability of intravesical 
pembrolizumab and the dose to be used in the randomised phase.  
 


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CANCER (NMIBC) 
 
 
Safety run-in  
The safety and tolerability of intravesical Pembrolizumab will be evaluated in six patients following TURBT for NMIBC 
prior to the main study commencing.  Treatment will be administered once weekly according to the following 
schedule.  Intra-patient dose escalation of intravesical Pembrolizumab will be performed in paired patient cohorts 
with the anticipated doses as shown below.    
 
Figure 1 
 
 
Cohort 
 
Patient 
Dose of Intravesical Pembrolizumab (mg) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
1 
1 
50 
50 
100 
100 
200 
200 
2 
50 
50 
100 
100 
200 
200 
2 
3 
100 
100 
200 
200 
200 
200 
4 
100 
100 
200 
200 
200 
200 
3 
5 
200 
200 
200 
200 
200 
200 
6 
200 
200 
200 
200 
200 
200 
Patients will be assessed for dose limiting toxicities (DLT) as well as for overall tolerability of the treatment.  A DLT is 
defined as a clinically significant, drug related, grade 4 haematological or > grade 3 non-haematological toxicity 
occurring within 7 days of administration of the first treatment at a given dose for that patient.  Treatment start dates 
will be staggered by at least one week between patients.  In addition, treatment of patients in cohort 2 and 3 will not 
commence until both patients in the preceding cohort have cleared the DLT period for the D15 dose. 
If more than 1 patient experiences a DLT at a certain dose, this dose will be declared non-tolerated and further 
escalation will cease.  Patients who have already commenced treatment at the same dose and are tolerating 
treatment may continue at this dose.  If a DLT occurs in either patient at the first dose of cohort 1, or in more than 1 
patient at subsequent doses, the TMG will meet to consider the available safety data and determine how to proceed.  
Recruitment of further patients to a cohort or investigation of intermediate doses or treatment intervals may be 
considered.     
When considering the dose to take forward to the randomised part of the study the TMG will also consider the overall 
tolerability of the treatment.  Patients must be able to receive at least 5 out of the 6 treatments for the regime to be 
defined as tolerable.   
Main study 
Once the TMG have considered the available safety data from the safety run-in cohort and confirmed the tolerated 
intravesical dose, the main study will open to recruitment, provided the TMG is in agreement. The TMG decision will 


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be documented in writing, and a record will be retained in the Trial Master File.   Patients will be randomised to 
receive either intravesical or intravenous pembrolizumab treatment post TURBT, having had a suitable marker lesion 
left in situ.  For at least five patients in each cohort, a second non-marker lesion will be left in-situ at the time of 
TURBT that will be resected on day 50. 
 
 
Figure 2: Schedule of treatment administration for main study.  *TURBT for resection of second non-marker lesion in 
at least 5 patients in each arm.  Black arrows denote treatment administration 
 
Please refer to the schedule of events and flow chart for details of the study visits and procedures. 
 
2.1 
Duration of patient participation 
Participants in the main study will be in the study for approximately 15 weeks from the time of first TURBT to the end 
of treatment visit.  Participants in the safety-run in period will be in the study for approximately 11 weeks from the 
time of their TURBT to the end of treatment visit. 
 
2.2 
Post-trial care and follow-up 
Following the end of treatment visit, patients will receive standard care.  However, patients in the main study will be 
followed up via the medical care team for 2 years or until disease recurrence, progression or death, whichever is 
sooner. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
Endpoints/ Outcome measures 
 
To assess the safety, tolerability and 
toxicities of intravesical and intravenous 
pembrolizumab after TURBT in patients 
with intermediate risk NMIBC  
 Incidence and severity of adverse events 
(NCI CTCAE v4.03) 
Secondary Objectives 
Endpoints 
 To provide a preliminary assessment of 
efficacy of treatment with intravesical 
pembrolizumab in patients with 
intermediate risk NMIBC  
 Complete response rate of marker-lesion 
as assessed clinically at TURBT and 
confirmed on biopsy of tumour bed 
 Recurrence and progression-free intervals  
 To provide a preliminary assessment of 
efficacy of treatment with intravenous 
pembrolizumab in patients with 
intermediate risk NMIBC 
 Complete response rate of marker-lesion 
as assessed clinically at TURBT and 
confirmed on biopsy of tumour bed 
 Recurrence and progression-free intervals  
Tertiary/Exploratory Objectives 
Endpoints 
 
Determine correlation between expression 
of PD-L1 and PD-1+ infiltrating 
 
Tumour/stromal cell PD-L1 expression 
and presence of PD-1+ infiltrating 


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lymphocytes and efficacy of 
pembrolizumab therapy after TURBT in 
intermediate risk NMIBC patients 
lymphocytes in pre, on and post 
treatment tumour samples measured by 
immunohistochemistry and FACS analysis  
 
Definition of gene expression signatures 
and genetic profiles capable of predicting 
efficacy of pembrolizumab treatment in 
NMIBC patients. 
 
Gene expression profiling and DNA 
sequencing on pre-treatment blood and 
tumour samples  
 
To evaluate the effects of pembrolizumab 
treatment on the immunological profile 
and tumour specific immune responses in 
patients with intermediate risk NMIBC  
 
Analysis of TCR repertoire and clonality 
of infiltrating T cells in resected tumour 
specimens, urine and normal bladder 
tissue 
 
Identification of myeloid or T cell 
responses in the tumour 
microenvironment associated with 
response to treatment 
 
Analysis of TCR repertoire and clonality 
of PBMC before, during and after 
treatment 
 
Analysis of cytokines in blood and urine 
 
To investigate the pharmacokinetics of 
intravesical pembrolizumab 
 
Analysis of blood levels of 
pembrolizumab during treatment 
 
4 
PATIENT SELECTION 
Written informed consent must be obtained before any study specific procedures are performed. The Investigator will 
determine patient eligibility based on the following criteria. Participants must satisfy the eligibility criteria prior to 
registration, randomisation and pre-dose at Day 1. 
4.1 
Eligibility criteria  
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial and comply with the protocol scheduled 
follow-up visits and examinations for the duration of the study 
2. Be  18 years of age on day of signing informed consent 
3. Have recurrent NMIBC for which adjuvant treatment post TURBT would be a reasonable treatment option 
4. Main study only: 
a. Have recurrent, multiple (minimum 2) tumours consistent with NMIBC  
b. Have at least one lesion of between 5-10mm in size clinically that can be left un-resected at TURBT 
as the marker lesion 
c. 
Have histologically confirmed low grade transitional cell NMIBC at original and any subsequent 
diagnosis 
5. Have a normal upper urinary tract (as evidenced by ultrasound or CT urography within 2 years prior to 
randomisation) and no evidence of tumour in prostatic urethra at flexible cystoscopy 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale 
7. Have adequate organ function as defined in the table below: 
Lab Test 
Value required 
Haemoglobin (Hb) 
≥ 9 g/dL without transfusion or EPO dependency 
Absolute neutrophil count (ANC) 
≥ 1.5 x 109/L 
Platelet count 
≥ 100 x 109/L 
Total bilirubin  
≤ 1.5 times the upper limit of normal (ULN) or direct 
bilirubin < ULN for subjects with total bilirubin 
levels > 1.5 x ULN 
Serum alanine aminotransferase (ALT) and/or 
serum aspartate aminotransferase (AST) 
≤ 2.5 x ULN 
 
 


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8. Female subjects of childbearing potential should have a negative urine or serum pregnancy test at screening 
and within 72 hours prior to receiving the first dose of study medication.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required 
9. Both male and female subjects of childbearing potential (Section 5.1) must be willing to use an adequate 
method of contraception as outlined in section 5.1 for the course of the study and until 120 days after the 
last dose of the study medication 
4.2 
Exclusion criteria: 
The subject must be excluded from participating in the trial if the subject: 
1. Has received prior radiotherapy to the pelvis 
2. Has significant urinary incontinence or known bladder instability 
3. Main study only: 
a. Has more than 2 out of 3 of the following present at the current time: 
i. ≥8 tumours 
ii. Tumour ≥3cm in size 
iii. Frequent recurrence (>1/year) 
b. Has a previous history of any of the following: T1 tumour, high grade/G3 tumour, carcinoma in situ, 
multiple recurrent large (>3cm) Ta, G1 or G2 tumours.   
c. 
Had a primary tumour of unknown pathological stage or grade 
d. Has disease for which resection of all visible tumours is not possible 
4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent 
and received study therapy or used an investigational device within 28 days of the first dose of trial 
treatment 
5. 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.  Subjects requiring use of 
inhaled or intranasal corticosteroids or local steroid injections would not be excluded 
6. Has a known history of active TB 
7. Has received intravesical BCG treatment within 30 days prior to the first dose of trial treatment 
8. Has hypersensitivity to pembrolizumab or any of its excipients  
9. Has had treatment with any other anti-cancer monoclonal antibody within 28 days prior to enrolment or who 
has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 
weeks earlier 
10. Has had treatment with prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks of administration of study drug or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
11. Has a known additional malignancy that is progressing or requires active treatment.  Exceptions include basal 
cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative 
therapy or in situ cervical cancer 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  Subjects with 
previously treated brain metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurological 
symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not 
using steroids for a t least 7 days prior to trial treatment.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability 
Serum creatinine OR 
Measured or calculated creatinine clearancea  
≤ 1.5 x ULN OR 
≥ 60ml/min for subject with creatinine levels > 1.5 x 
institutional ULN 
Albumin 
≥ 25g/L 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) and 
Activated Partial Thromboplastin Time (aPTT) 
≤ 1.5 x ULN unless subject is receiving anticoagulant 
therapy as long as PT or APTT is within 
therapeutic range of intended use of 
anticoagulants 
a Creatinine clearance should be calculated as per institutional standard 


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13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of 
disease modifying agents or immunosuppressive drugs).  Replacement therapy (e.g. thyroxine, insulin or 
physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment 
14. Has a known history of, or any evidence of active, non-infectious pneumonitis 
15. Has an active or intractable infection requiring systemic therapy 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in 
the best interest of the subject to participate, in the opinion of the treating Investigator 
17. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the 
requirements of the trial 
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the 
trial, starting with the pre-screening or screening visit through to 120 days after the last dose of trial 
treatment 
19. Has received prior therapy with an anti-PD-1, anti PD-L1, or anti-PD-L2 agent 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
21. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected) 
22. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
4.3 
Protocol deviations and waivers to entry criteria 
Protocol adherence is a fundamental part of the conduct of a clinical study.  Changes to the approved protocol need 
prior approval unless for urgent safety reasons. 
 
Investigators must contact OCTO to obtain guidance and/or clarification as necessary if unsure whether the patient 
satisfies all the entry criteria and to clarify matters of clinical discretion.  OCTO will contact the Chief Investigator or 
clinical coordinators as necessary.  Investigators should not request a protocol waiver to enter a patient who does not 
satisfy the selection criteria. 
 
The Investigator must document and explain any deviations/violations from the approved protocol. The Investigator 
should promptly report any important violations that might impact patient safety, data integrity or be a possible 
serious breach (see 21.7 below) to the Trial Office.  
4.4 
Re-screening if patient does not meet inclusion/exclusion criteria first time round 
If a patient does not meet the laboratory haematological and biochemical inclusion/exclusion criteria the first time 
round, he/she can be re-screened within the 30-day screening period and does not need to be reconsented.  Patients 
who fail at rescreening or who fail any other criteria first time round are ineligible for this recurrence episode but may 
be rescreened at the time of any subsequent recurrence; in these circumstances, reconsent should be sought. 
4.5 
Patient registration and randomisation procedure 
Potential participants will be identified by their clinical care teams following a diagnosis of recurrent NMIBC at the 
time of flexible cystoscopy under local anaesthetic, prior to admission for surgical management.  Discussion at 
multidisciplinary (MDT) meetings will aid identification of potential participants.  Patients for whom PEMBLA is a 
suitable option will be approached and given time to consider participation.     
 
A screening log must be kept of all patients considered for the study including any that are subsequently excluded; the 
reason for exclusion must be recorded on this form.  A copy of the screening log should be sent to the Trial Office on 
request, but without patient identifiers. The original must be retained on site. 
 
Patients will be registered & randomised to the trial in a two part process. Before registering/randomising a patient to 
the study treatment, the Principal Investigator or designee will confirm eligibility. If in any doubt the Chief Investigator 
must be consulted before entering the patient.  Details of the query and outcome of the decision must be 
documented on the registration/ eligibility checklist. 
 
 
4.5.1 
Patient Registration (Safety Run-in and Main Study) 


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The Day -14 TUBRT must not take place until the registration process is complete. 
 
To register a patient to the trial, the site must email the completed Registration Form to the Trial Office: octo-
pembla@oncology.ox.ac.uk  The patient will then be registered to the trial and assigned a unique trial number by the 
Trial Office.  Patients in the Safety run-in will also be assigned to the appropriate treatment cohort.  The site will be 
informed by email of the patient’s unique trial number (and treatment cohort if applicable) by the Trial Office. 
 
The patient’s trial number must be specified on all CRFs and SAEs forms submitted for the patient and in all relevant 
correspondence with the Trial Office. 
 
4.5.2 
Patient Randomisation (Main Study Only) 
 
Cycle 1 Day 1 Trial Treatment must not start until this randomisation process is complete, and  should begin 14 days 
after TURBT, and within 7 days of randomisation or as close as possible to this date. 
 
To randomise a patient to the trial, once the TUBRT procedure has taken place and continued eligbility for the trial is 
confirmed, 
the 
site 
must 
email 
the 
completed 
Randomisation 
Form 
to 
the 
Trial 
Office: 
octo-
pembla@oncology.ox.ac.uk  The patient will then be randomised to  either Arm A or Arm B trial treatment..   
 
4.5.3 
Safety run in phase 
The first six patients will not be randomised and will receive intravesical pembrolizumab as part of the safety run-in 
phase.  
 
4.5.4 
Randomisation 
 
Randomisation into the study will only begin after the trial management group has considered the safety analysis of 
the run-in cohort. Eligible patients will be randomised 1:1 to receive intravenous pembrolizumab or intravesical 
pembrolizumab following TURBT.  Minimisation will be performed by study centre.   
 
5 
TRIAL ASSESSMENTS AND PROCEDURES 
Please refer to the Schedule of Investigations given at the front of this protocol. Details of all protocol evaluations and 
investigations must be recorded in the patient’s medical record for extraction onto the CRF.  
5.1 
Informed consent 
Potential participants will be given a current, approved version of the patient information sheet and consent form. 
They will also receive clear verbal information about the study detailing no less than: the nature of the study; the 
implications and constraints of the protocol; the known side effects and any risks involved in taking part.  It will be 
explained that they will be free to withdraw from the study at any time, for any reason, without prejudice to future 
care, and with no obligation to give a reason for withdrawal. They will have at least 24 hours to consider the 
information provided and the opportunity to question the Investigator, their GP or other independent parties before 
deciding whether to participate. 
 
The Investigator who obtains consent must be suitably qualified and experienced.  All delegates must be authorised 
by the Chief/Principal Investigator to obtain consent.  The Investigator is responsible for ensuring that the trial 
consent procedures comply with current applicable GCP, Regulatory and Ethical requirements.  Informed consent 
discussions and outcomes must be well documented in the medical record.  The Investigator must be satisfied that the 
patient has made an informed decision before taking consent.  The patient and the Investigator must personally sign 
and date the current approved version of the informed consent form in each other’s presence.  A copy of the 
information and signed consent form will be given to the participant. The original signed consent form will be retained 
at the trial site, with copies held in both the medical record and Investigator Site File (ideally the original if local policy 
permits).  


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Contraceptive/ Pregnancy counselling 
Pembrolizumab may have adverse effects on a foetus in utero.  Furthermore, it is not known if pembrolizumab has 
transient adverse effects on the composition of sperm.   
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether 
due to having had a vasectomy or due to an underlying medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal -defined as at least 12 months with no menses without an alternative medical cause; in women < 
45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. 
In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3)   has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating a 
partner, respectively, while receiving study drug and for 120 days after the last dose of study drug by complying with 
one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (oestrogen/progestin pill or progestin-only pill), contraceptive 
skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Declaration of abstinence for the duration of exposure to the IMP, periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the foetus (unborn baby) 
if pregnancy were to occur during the study.  In order to participate in the study, subjects of childbearing potential 
must adhere to the contraception requirement (described above) from the day of study medication initiation (or 14 
days prior to the initiation of study medication for oral contraception) throughout the study period and for 120 days 
after the last dose of trial drug.  If there is any question that a subject of childbearing potential will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study. 


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Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will immediately be 
removed from the study.  The site will contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated.  The outcome of the pregnancy will be reported to the Trial Office 
without delay and within 24 hours if the outcome is a serious adverse event (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
The study Investigator will make every effort to obtain consent to follow the outcome of the pregnancy and report the 
condition of the foetus or newborn to the Trial Office.   If a male subject impregnates his female partner, the study 
personnel at the site must be informed immediately and the pregnancy reported to the Trial Office as described above 
and in Section 13. 
5.2 
Screening evaluations  
For all parts of the study the following screening and eligibility assessments must be performed/obtained within the 
30 days before the patient undergoes TURBT:  
 
Written informed consent  
 
Demographic details including age, sex, self-reported race/ethnicity, history of occupational exposure to 
aromatic amines  
 
Medical History to include cancer history, prior cancer therapies and procedures, smoking history, clinically 
significant past medical history and concomitant medical conditions  
 
Concomitant medications 
 
Physical examination 
 
Height and weight 
 
ECOG performance status 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate, respiratory rate, oxygen saturations and 
temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4)  
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
Overall assessment of patient eligibility according to inclusion/exclusion criteria 
5.3 
Evaluations during the study 
 
Day -14 - TURBT  
A cystoscopy and TURBT will be performed on day -14 of the study in accordance with local hospital protocols.  This 
should be performed no later than 30 days following diagnosis of recurrent NMIBC; if outside of this window, please 
contact the PemBla Trial Office for advice.  The following will also be performed: 
 
 
Blood for immunoprofiling 
 
Bladder barbotage (instillation and recovery of 4 x 50ml instillations of normal saline into the bladder) prior 
to resection  
 
A biopsy of the normal bladder epithelium, to be sent to the central laboratory for research purposes. 
 
In addition, for patients in the Safety Run-in Study only: 
 
 
All tumour(s) should be resected and a sample sent to the local laboratory for histological review and 
grading.  Any tissue excess to diagnostic requirements will be sent to the central laboratory for 
immunoprofiling, gene expression profiling and DNA sequencing. 
 
In addition, for patients in the Main Study only - all patients: 
 
At the time of TURBT an appropriate marker lesion should be selected.  This should be a solitary lesion 
measuring between 5-10mm which can be left un-resected without being disturbed/touched during 


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resection of the other lesions.  If this is not technically possible all tumours should be resected and the 
patient excluded from the study. 
 
The size, location and morphology of the marker lesion should be documented in a bladder diagram.  Where 
possible, photographs should be taken.  Other non-marker lesion tumours should also be documented on 
the bladder diagram.    
 
For patients with 3 or more tumours who have consented to having a second non-marker lesion left in-situ, 
this should be identified, recorded on the bladder diagram and left un-resected. 
 
All other lesions should be resected.  A sample of one of the resected tumours should be sent to the local 
laboratory for tumour grading and fixation for subsequent PD-1/PD-L1 testing.  All other  resected tumour 
samples will be sent to the central laboratory for immunoprofiling, gene expression profiling and DNA 
sequencing.  
 
Day -13 - Day-1  
During this period, the pathology results from the resected tumours should be reviewed.  For the main study only, if 
any of the tumours are found to be high grade/G3 or CIS, the patient will be excluded from further participation in the 
study and arrangements should be made to resect the marker lesion and any other non-marker lesion that was left at 
the earliest opportunity.  Subject to on-going eligibility, the patient will be randomised to either intravesical or 
intravenous Pembrolizumab.    
 
Evaluations on day 1 (All patients) 
 
Baseline AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT 
 
Blood for germline DNA  
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
Blood samples for immunoprofiling  
 
Blood samples for research assessment (intravesical arm only) pre-dose and 2hr post dose 
 
Urine sample for cytokines - Intravesical patients pre-dose and post-dose sample (after the drug has been 
voided from the bladder) will be collected (visits thereafter only post-dose will be collected).  For intravenous 
treatment patients, urine for cytokines collected pre-dose only. 
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 8 and 15 (Patients receiving intravesical treatment only)  
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Urine sample for cytokines – post dose only 
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 22 (Patients receiving intravenous or intravesical treatment) 


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 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4) 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Urine sample for cytokines   - Intravenous patients pre-dose only, Intravesical post-dose only.  
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 29 and 36 (Patients receiving intravesical treatment only) 
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Blood samples for research assessment  - (d36 only) pre dose only 
 
Urine sample for cytokines  - post dose only 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required (Day 29 only) 
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 43 (Patients receiving intravenous treatment only) 
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4) 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Urine sample for cytokines – pre-dose only 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 50 (Patients who have consented to resection of second non-marker lesion only) 
 
Patients who consented to having a second non-marker lesion left at the time of the original TURBT will 
undergo a cystoscopy for resection of the non-marker lesion which will be sent for research 
 
Bladder barbotage and a biopsy of normal bladder epithelium will be performed and sent for research 
 
Blood samples for immunoprofiling 
 
Urine sample for cytokines – to be taken pre-operatively 
 


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Evaluations on day 64 (Main study only – all patients) 
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4) 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Urine sample for cytokines - Intravenous patients pre-dose only, Intravesical post-dose only. 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
Administration of study agent and monitoring for any immediate adverse events 
 
Evaluations on day 85 (Main study only – all patients) 
On day 85 of the main study a cystoscopy and TURBT will be performed in accordance with local hospital protocols.  In 
addition: 
 
The size and morphology of the marker lesion should be documented in a bladder diagram with photographs 
where possible.  Any new lesions should also be documented.   
 
Bladder barbotage should be performed prior to resection of any residual marker lesion 
 
If still visible, the marker lesion should be resected and sent to the central laboratory for immunoprofiling 
 
A biopsy will be performed of normal bladder epithelium and sent to the central laboratory for research 
purposes 
 
If the marker lesion is no longer visible, biopsies of the site of the previous tumour bed should also be 
performed and sent to the local laboratory for histological assessment and the central laboratory for research 
purposes 
 
Blood samples should be taken for immunoprofiling  
 
Urine sample for cytokines – taken pre-operatively 
 
5.4 
End of study/treatment evaluations  
 
5.4.1 
Safety run-in 
The end of study visit for patients on the safety run-in part of the study will be performed on day 64 (or within 7 days 
thereafter).  Evaluations will include: 
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4) 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Blood samples for immunoprofiling  
 
Urine sample for cytokines  
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
5.4.2 
Main study (Intravenous and Intravesical treatment) 


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The end of treatment visit for the main study will be performed on day 92 (or within 7 days thereafter) for all patients.  
Evaluations will include: 
 
AEs 
 
Review of concomitant medications  
 
Physical examination 
 
ECOG performance status 
 
Vital signs - systolic / diastolic BP, pulse rate, respiratory rate, oxygen saturations and temperature 
 
Haematology – Full blood count (FBC), clotting screen 
 
Biochemistry – sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, 
alkaline phosphatase (ALP), AST and/or ALT, thyroid function tests (TSH, T3 and T4) 
 
Urinalysis (Blood, White Cells, Protein, Nitrites, pH), culture and sensitivity 
 
Pregnancy test (for female subjects of childbearing potential only): serum or urine Human Chorionic 
Gonadotropin (HCG) test.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required 
 
Follow-up evaluations 
After the end of the treatment visit, patients will be followed up as per local protocols for standard of care at the 
discretion of the Investigator.  This would ordinarily consist of cystoscopy every three months.  Safety reporting will 
continue for 90 days post end of treatment. Data on the recurrence-free interval and progression-free interval will be 
collected for 2 years or until disease recurrence, progression, death or closure of the trial, whichever is sooner.   
 
Collection of an optional tumour sample at the time of recurrence or progression for research purposes will be 
performed if the patient provides consent for this.  The optional tumour sample would be collected at the time of a 
standard care surveillance cystoscopy or resection if the patient had a repeat TURBT in standard care. It will be made 
clear at the time of consent that the patient can change their mind at any point.   
5.5 
Evaluations on early withdrawal 
If a patient is withdrawn from the treatment or the study early, the end of treatment evaluations in section 5.4 should 
be performed as soon as possible and within 28 days. Any/all remaining marker lesions should be resected as soon as 
possible as per standard care i.e. final TURBT should be brought forward.    
 
6 
EARLY PATIENT WITHDRAWAL 
Treatment Withdrawal 
During the course of the trial, a patient may withdraw early from treatment.  This may happen for a number of 
reasons, including: 
 
Unacceptable toxicity 
 
AE/SAEs requiring discontinuation 
 
Loss to follow-up 
 
Significant protocol deviation or inability to comply with trial procedures 
 
Clinical decision 
 
Patient decision 
 
Patients may choose to stop treatment and/or study assessments but may remain on study follow-up. When the 
patient stops treatment early, the ‘End of Treatment’ Form needs to be completed, and any other relevant CRFs (for 
example SAE Form).  The reason for withdrawing from treatment early should be clearly documented in the medical 
records.  Excepting withdrawal of consent, patients will be followed-up for 2 years or until disease recurrence, 
progression or death, whichever is sooner.   
 
Consent Withdrawal 
Consent withdrawal means that a patient has expressed a wish to withdraw from the study completely.   Under these 
circumstances, the site needs to document all relevant discussions in the patient notes and notify the Trial Office, 
which will allow the office to mark all future CRFs as not applicable.  
 


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CANCER (NMIBC) 
Under these conditions, Investigators are still required to follow up any SAEs until resolution. 
6.1 
Patient evaluability and replacement 
During the safety run in phase patients who do not receive at least 5 out of the 6 scheduled treatments, except for 
reasons of drug-related toxicity, will be replaced such that there are 6 patients evaluable for tolerability.  During the 
main study all participants who receive one dose of either intravenous or intravesical pembrolizumab will be 
evaluable.  Patients who are not evaluable for the primary endpoint, i.e. any patient that withdraws from the main 
study before receiving treatment with the study drug, will be replaced. 
 
7 
SAMPLES FOR LABORATORY ANALYSIS 
7.1 
Samples to be analysed in local Trust’s laboratories 
Diagnostic Laboratories 
Bloods samples for haematology and biochemistry analysis and urine samples for culture and sensitivity will be 
labelled with standard patient identifiers and sent to the hospital diagnostic laboratory.  Results will be processed in 
the standard way and entered into the routine hospital reporting system.  Samples will be stored, held, reported and 
subsequently destroyed in accordance with standard local laboratory practice.  
Pathology 
A sample of one of the resected tumours from the baseline TURBT should be sent to the local laboratory for tumour 
grading and fixation for subsequent PD-1/PD-L1 testing. In addition, in the case of complete clinical response at the 
day 85 TURBT, a biopsy of the tumour bed will be performed and sent to the local laboratory for histological analysis. 
Samples should be labelled, processed and reported according to local hospital protocols.        
7.2 
Samples to be sent to and analysed in Central Analytical laboratories 
Detailed instructions for sample handling can be found in the Sample Handling Manuals for the trial.   
 
PD-L1 expression analysis  
The following samples will be sent to Qualtek for analysis  
 
Formalin fixed paraffin embedded (FFPE) tumour sample for PD-L1 expression analysis (5 unstained slides) 
Tumour samples will be fixed in formalin and paraffin embedded at site  
 
Research Samples for translational research at Oxford 
All other samples gifted for research will be delivered into the custodianship of  Prof Vincenzo Cerundolo  and 
managed by his team at the MRC Human Immunology Unit laboratory at the Weatherall Institute of Molecular 
Medicine. These will include:  
 
Blood samples for germline DNA analysis 
 
Blood samples for isolation of peripheral blood mononuclear cells (PBMC) and cytokine measurement 
 
Fresh tumour samples for DNA sequencing, gene expression profiling,  T cell receptor (TCR) analysis and 
functional studies 
 
Fresh biopsies of normal bladder epithelium for immunoprofiling 
 
Fresh biopsies of tumour bed in event of CR for immunoprofiling 
 
Urine for cytokine measurement  
 
Recovered bladder barbotage instillations for isolation and characterisation of lymphocytes and/or tumour 
cells 
 
Blood samples for research taken from patients receiving intravesical treatment pre-dose and 2 hours post-
dose for the first treatment, and pre-dose at cycle 6 (d36). Research use to be determined as directed by the 
custodian, expected analysis to be pharmacokinetic assay of the systemic absorption of pembrolizumab or 
other before/ after time critical analyses. 
7.3 
Pharmacodynamic and translational assays 
Pharmacodynamic and translational assays may include but are not limited to the following: 
 
Immunoprofiling 
To assess the extent of T cell activation mediated by pembrolizumab and changes in the immunological 


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profile in response to treatment, PBMC will be isolated from blood before, during and after treatment.  
Tumour infiltrating lymphocytes will also be extracted from tumour samples using established protocols.  
Fluorescence-activated cell sorting (FACS) and mass cytometry (CyTOF) will be used to identify T cell subsets 
in peripheral blood and tumour, T cells will be isolated and the TCR repertoire will be analysed.  Cytokines will 
also be measured from blood and urine samples. 
 
DNA sequencing   
Whole genome sequencing will be performed on blood and tumour samples.  Gene expression profiling will 
also be performed.    
7.4 
Summary of samples/assays to be taken during the study  
Assay/sample handling and storage will be managed according to separate written instructions.  
7.5 
Labelling and confidentiality of samples sent 
All samples sent to analytical laboratories will be labelled with the trial code, trial patient number, Year of birth, and 
date/time taken.  Should a laboratory receive any samples carrying patient personal identifying data the recipient 
must immediately obliterate this information and re-label with a trial label.  
7.6 
Clinical reporting of exploratory research assay results 
The results of the research assays are exploratory and are not intended to influence the individual patient’s medical 
care. Findings will not be reported routinely to the responsible clinician except in the unlikely event that the result 
might be beneficial to the patient’s clinical management. 
7.7 
Samples for Biobanking 
Samples are not being collected specifically for biobanking, however patients will be asked to consent for the transfer 
of any surplus tumour biopsy and blood samples from the trial central laboratories to a licensed biobank for future 
use. 
7.8 
Trial sample custodianship and retention at end of study 
All research samples collected during this trial are considered a gift to the University of Oxford. The trial Academic 
Lead Professor Enzo Cerundolo is the responsible trial sample custodian. He is authorised to oversee trial sample 
retention, release for exploratory assays within the terms of the trial ethics approval. He will comply with the sponsor 
and applicable HTA guidelines and regulatory requirements.   Any decision to vary from the planned exploratory 
analyses should be guided by the Chief Investigator, TMG and other trial stakeholders and documented by the 
Custodian.  
 
Laboratories are instructed to retain any surplus samples pending instruction from the sample custodian on use, 
storage or destruction.  It is possible that new or alternative assays may be of future scientific interest. At the end of 
the research study any surplus samples may be retained for use in other projects that have received ethical approval.  
Hence, any surplus study samples may be transferred to a licensed tissue bank where they will be managed in 
accordance with applicable host institution policies and the Human Tissue Act (HTA) requirements.  
7.9 
Withdrawal of consent for sample collection and/or retention 
A patient may withdraw consent to provide samples for research at any time without giving a reason. The Investigator 
must ensure that their wishes are recorded in the medical record and will inform the Trial Office accordingly. The 
Investigator should discuss with patients the valuable use of samples that have already been provided and under 
circumstances where these samples have already been processed, it would not be possible to destroy such samples. 
 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS)  
8.1 
Name of IMPs 
The investigational medicinal product being used in this trial is pembrolizumab.  It will be supplied as a solution for 
Infusion 


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8.2 
Treatment dose and duration 
 
 
 
 
 
 
 
 
* Subject to recommendation by the TMG following analysis of safety and tolerability data from the safety run-in 
cohort. 
 
Dose modifications for drug related toxicity are permitted as detailed in section 8.5.   
8.3 
Management of drug administration 
Trial treatment should begin 14 days after TURBT, and within 7 days of registration/randomisation or as close as 
possible to this date.  Subsequent treatments should be administered according to the schedule shown in Figure 1 for 
the safety run-in cohort, and Figure 2 for the main study, in Section 2.  For patients receiving intravenous treatment, 
pembrolizumab may be administered up to 3 days before or after the scheduled date for administrative reasons.  For 
patients receiving intravesical treatment, pembrolizumab may be administered up to 1 day before or after the 
scheduled date if required for administrative reasons.  
8.3.1 Intravesical treatment 
The Pembrolizumab suspension should be made up in a syringe with a luer lock on the end. A urinary catheter will be 
inserted into the urethra under aseptic conditions according to local hospital protocol and the bladder drained 
completely.  Using a catheter adapter with the syringe, the pembrolizumab suspension will then be instilled into the 
bladder via the catheter over a period of no more than 5 minutes.  After instillation the catheter will be removed and 
the patient instructed to retain the instilled suspension in the bladder for a period of 2 hours.  During this period care 
should be taken to ensure that the instilled suspension has sufficient contact with the whole mucosal surface of the 
bladder.  The patient should be encouraged to mobilise or if lying down to rotate between prone, supine, left lateral 
and right lateral positions every 15 minutes.  After 2 hours the patient should void the instilled suspension directly 
into a toilet.   
The patient should be advised to limit their fluid intake for 4 hours prior to instillation and until bladder evacuation is 
permitted (i.e. 2 hours after instillation).   
For the patient’s first instillation of intravesical treatment in all parts of the study, and at any increased dose level for 
that patient during the safety run-in, the patient should be observed for 2 hours after administration of 
pembrolizumab with blood pressure, pulse, respiratory rate, oxygen saturations and temperature to be monitored 
every 15 minutes for first 30 minutes and then every 30 minutes until the bladder is voided.  For subsequent 
instillations vital signs should be performed before treatment and thereafter as clinically indicated. 
After bladder evacuation, the next first voided urine sample should be collected for immunoprofiling.   
Intravenous treatment 
Pembrolizumab will be administered as an intravenous infusion using an infusion pump over 30 minutes with a 
window of -5 and + 10 minutes through a peripheral line or in-dwelling catheter containing a sterile, non-pyrogenic, 
low protein binding 0.2 to 5 micron in-line or add on filter.  No other drugs should be administered through the same 
infusion line.  Whenever possible, the lowest infusion rate should be used that will allow completion of the infusion 
within the 30 minutes.  Use 30ml normal saline to flush the infusion line at the end of the infusion.   
Management of infusion reactions 
Across clinical studies with pembrolizumab in approximately 5000 patients, severe infusion-related reactions have 
been reported in less than 0.1% of patients. For severe infusion reactions, the infusion should be stopped and 
pembrolizumab permanently discontinued.  Patients with mild or moderate infusion reactions may continue to 
receive pembrolizumab with close monitoring; premedication with an antipyretic and/or antihistamine may be 
considered 
according 
to 
local 
protocols. 
 
See 
section 
9.1 
for 
further 
guidance.
Study Drug 
Dose 
Dose frequency 
and schedule 
Route of 
administration 
Administer 
over 
Use 
Pembrolizumab 
200mg 
Q3W x 4 doses 
IV infusion 
30 minutes 
Experimental 
Pembrolizumab 
50-200mg* 
Q1W* x 6 doses  
Further dose 
D64 
Intravesical 
5 minutes 
Experimental 


                              
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8.4 
Special precautions 
Not applicable 
8.5 
Dose modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an immunologic aetiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment.  For all patients in the study, whether receiving intravenous or intravesical treatment, pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per the table below.  See section 9.1 for supportive care guidelines, including use of corticosteroids.   
 
 
General instructions: 
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. 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.  
3. 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. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAE) 
Action taken to 
pembrolizumab 
Management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants 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 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus). 
 
Participants with ≥ Grade 2 diarrhea 


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Grade 4 
Permanently 
discontinue 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
 
Participants 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. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids (initial 
dose of 0.5- 1 mg/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 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants with 
T1DM 
 Administer anti-hyperglycemic in 
participants with hyperglycemia 
 
 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
 
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
 
Monitor for signs and symptoms of thyroid 
disorders. 
 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
 
Monitor for signs and symptoms of thyroid 
disorders. 
 


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Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4 
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 type and severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based on 
the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Gullain-
Barre Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
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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Intravesical pembrolizumab 
The following additional specific guidance applies to patients receiving intravesical pembrolizumab.   
In the event of grade 2 haematuria, dysuria, urinary retention, urinary frequency/urgency, or bladder spasm that 
persists beyond 72 hours following intravesical treatment, the next scheduled instillation should be omitted.  
Symptoms must have resolved to a maximum of grade 1 before treatment resumes at the next scheduled timepoint.  
Irritative bladder symptoms can be managed by anticholinergic or antispasmodic therapy.  In patients experiencing 
haematuria, it is important to perform a urine culture to exclude bacterial cystitis.  
If the patient has a confirmed urinary tract infection treatment should be omitted to allow for resolution of the UTI 
with antibiotics.  If catheterisation is traumatic, treatment should be omitted and subsequent cycles given as 
scheduled.   Any patient who misses more than one dose of intravesical pembrolizumab should be discontinued from 
treatment.   
8.6 
Management of overdose 
For the purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab.  Whilst no specific information is available on the treatment of overdose of pembrolizumab, doses of 
up to 10mg/kg have been safely administered intravenously in other studies.  In the event of overdose, the subject 
should be observed closely for signs of toxicity and appropriate supportive treatment should be provided if clinically 
indicated. 
 
All reports of overdose with or without an adverse event must be reported within 24 hours to the Trial Office as an 
Event of Clinical Interest on an SAE Form (see section 12.6.1).  The Trial Office will report the event to MSD within the 
agreed timescales.   
 
9 
OTHER TREATMENTS (NON-IMPS) 
9.1 
Support medication 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating Investigator.  
Suggested supportive care measures for the management of adverse events with potential immunologic aetiology are 
outlined below.  Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  1mg/kg per day of methylprednisolone (or oral equivalent) is suggested as an initial treatment dose 
for most adverse events of potential immune aetiology.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts should be made 
to rule out other causes such bacterial or viral infections, which might require additional supportive treatment.  The 
treatment guidelines are intended to be applied when the Investigator determines the events to be related to 
pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the Investigator does not need to follow the 
treatment guidance (as outlined below).  Refer to section 8.5 for dose modification. 
 
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or skin biopsy as part of 
evaluation of the event. 
 
 
Pneumonitis:  
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional anti-
inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
Diarrhoea/Colitis:  


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Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhoea, abdominal 
pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and 
ileus).   
o 
All subjects who experience diarrhoea/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.  For Grade 2 or higher diarrhoea, consider GI consultation and endoscopy to confirm or 
rule out colitis. 
o 
For Grade 2 diarrhoea/colitis, administer oral corticosteroids.  
o 
For Grade 3 or 4 diarrhoea/colitis, treat with intravenous steroids followed by high dose oral 
steroids.   
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycaemia, 
if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o 
For T1DM or Grade 3-4 Hyperglycaemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycaemia associated with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide.  
 
Hypophysitis: 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
o 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function 
(at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and 
for clinical signs and symptoms of thyroid disorders. 
o 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
Hepatic: 
o 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline values 
(consider weekly). 
 
Treat with IV or oral corticosteroids 
o 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  


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o 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks. 
 
Renal Failure or Nephritis: 
o 
For Grade 2 events, treat with oral corticosteroids. 
o 
For Grade 3-4 events, treat with intravenous corticosteroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.  
 
Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 
o 
If patient has signs or symptoms of SJS or TEN withhold pembrolizumab and refer the patient for 
specialist care for assessment and treatment 
o 
If SJS or TEN is confirmed permanently discontinue treatment with pembrolizumab 
 
Immune-mediated myocarditis management 
o 
For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude other 
aetiologies, and administer corticosteroids as appropriate. 
 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion.  
The table below shows treatment guidelines for subjects who experience an infusion reaction associated with 
administration of pembrolizumab. 
 
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 infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, opiates, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Paracetamol 
 
Opiates 
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 one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and 
the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Chlorphenamine 4 mg PO or 
10mg IV 
 
Paracetamol 1000g PO 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Paracetamol 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; inotrope or 
ventilatory support indicated 
 
Opiates 
 
Oxygen 
 
Inotropes 
 
Corticosteroids 
 
Adrenaline 
 
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. 
Subject is permanently discontinued from 
further trial treatment administration. 
 
9.2 
Concomitant medication and non-drug therapies 
Concomitant medication may be given as medically indicated taking account of prohibited therapies (section 9.3).  All 
patients will be asked to provide a complete list of prescription and over-the-counter medications that have been 
taken within the previous 4 weeks prior to the first treatment visit.  They must also inform the Investigator about any 
new medication started while in the trial. 
 
Details (including indication, doses, frequency and start/stop dates) of concomitant medication taken during the trial 
until the completion of the end of study visit must be recorded in the medical record and the appropriate CRF. 
9.3 
Prohibited therapies 
Patients should not be prescribed any other anti-cancer or investigational therapies while participating in this study. In 
addition, the following advice should be noted: 
10. Live vaccines should not be given within 30 days prior to the first dose of the trial treatment, while 
participating in the trial and for 6 months after the end of treatment.  Examples of live vaccines include, but 
are not limited to, the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and oral 
typhoid vaccine.  Seasonal influenza vaccines are generally killed virus vaccines and are allowed; however 
intranasal influenza vaccines are live attenuated vaccines, and are not allowed. 
11. Glucocorticoids for any purpose other than to modulate symptoms from an adverse event suspected to be of 
immunologic aetiology should be avoided (excepting inhaled or intranasal corticosteroids or local steroid 
injections).  The use of physiological replacement doses of corticosteroids may be approved after 
consultation with the Trial Office.  
 
Subjects who, in the assessment by the Investigator, require the use of any of the aforementioned treatments for 
clinical management should be removed from the trial.   
The use of intravesical BCG should be avoided for 30 days following the last dose of study drug. 
9.4 
Drug Interactions 
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab.  Subjects should 
maintain a normal diet unless modifications are required to manage an AE such as diarrhoea, nausea or vomiting. 
10 DRUG MANAGEMENT 
10.1 Drug supplies 
Pembrolizumab will be supplied free of charge by Merck as summarised below  
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Infusion 
All supportive medication is to be sourced and funded locally. 


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10.2 Drug ordering   
Drug supply details will be provided by the Trial Office prior to shipping, and all subsequent queries should be directed 
to the PEMBLA trial team.  If a vial of pembrolizumab is accidentally destroyed, i.e. by dropping the vial or through 
contamination, the pharmacist should contact the Trial Office on 01865 227190 or email octo-
pembla@oncology.ox.ac.uk immediately so that replacement patient supplies may be arranged. 
Initial supplies of pembrolizumab are sent out by Merck (MSD) after they have been informed by the Trial Office that 
all approvals are in place.  Subsequent supplies will be provided in batches organised by the Trial Office. Pharmacies 
will be responsible for monitoring and requesting stock as required, following the re-ordering instructions in the 
Pharmacy Manual. Contact the Trial office on 01865227190 or by email on octo-pembla@oncology.ox.ac.uk to 
request an order to be placed. Standard delivery time is within 5 working days of the order being placed.   
10.3 IMP Receipt 
Receipt of trial medication must be recorded by an authorised person at the trial site.  IMP shipments will arrive with 
an ‘Acknowledgement of Receipt’ form that should be emailed to octo-pembla@oncology.ox.ac.uk to confirm receipt.  
If supplies are damaged on arrival, contact the PemBla Trial Office. Damaged supplies should be destroyed on site and 
a drug destruction form completed. 
10.4 Handling and storage 
Clinical trial supplies must be stored in a secure, limited-access location under the storage conditions specified on the 
label.  Clinical trial supplies may not be used for any purpose other than that stated in the protocol.  If a temperature 
excursion occurs, please quarantine the affected drug as per local procedures and contact the PemBla Trial Office on 
01865 227190 or email octo-pembla@oncology.ox.ac.uk  
10.5 Dosing dispensing  
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in a single-use Type I glass 
vial containing 100mg/4ml of Pembrolizumab.  The product is a preservative-free solution which is essentially free of 
extraneous particulates.  Solution for Infusion vials should be stored at refrigerated conditions (2-8°C) and in the 
original box to ensure the drug product is protected from light.   
 
Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride (normal saline) and the final 
concentration of pembrolizumab in the infusion solution should be between 1mg/ml and 10mg/ml.  For intravesical 
infusions the final volume of infusion instilled will be 40ml.   
 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes 
room temperature storage of reconstituted drug product solution in vials, room temperature storage of admixture 
solutions in the IV bags and the duration of infusion. In addition, IV bags may be stored under refrigeration at 2°C to 
8°C for up to 20 hours.  If refrigerated, allow the IV bags to come to room temperature prior to use.   
 
For further information, including particulars for intravesical administration, please see the pharmacy manual.   
10.6 Drug accountability 
Full patient-specific drug accountability records must be maintained for pembrolizumab.  Hospitals may amend the 
Drug Dispensing Logs provided, or use their own documentation if it captures all the information requested on the 
Drug Dispensing Logs and is given prior approval by the Trials Office.  The drug dispensing and inventory logs should 
be kept up to date and must contain the following information; patient identifier, date and quantity received at site, 
date and quantity dispensed, date and quantity returned/destroyed at site.  At the conclusion of the study the overall 
numbers of drug shipped to the centre, the number dispensed and the number destroyed will be provided by the 
pharmacy. An account must be given of any discrepancy. 
10.7 Drug destruction 
Any unused drug remaining in a used vial should not be used for another infusion of the same subject or different 
subject and should be disposed of at site according to local hospital policy.  During the trial or upon completion or 
termination of the study, written permission must be gained from the Trial Office before any  unused and/or partially 


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used and any expired investigational product is  destroyed. Once permission is gained, local hospital destruction policy 
can be followed.  A dated certificate of disposal should be completed and retained in the Pharmacy File.  As per 
Section 10.3, if supplies are damaged on arrival, contact the PemBla Trial Office. Upon permission from the trial office, 
damaged supplies should be destroyed on site and a drug destruction form completed. 
 
10.8 Occupational safety 
Vein extravasation and accidental spillages of IMP should be dealt with according to hospital policy.  
The product is not expected to pose an occupational safety risk to site staff under normal conditions of use and 
administration. 
10.9 Product quality complaints: 
Any quality complaints or comments concerning the pembrolizumab clinical drug supplies for the study should be sent 
to the Trial Office in the first instance: octo-pembla@oncology.ox.ac.uk  
11 EVALUATION OF RESPONSE` 
11.1 Tumour assessment 
A clinical assessment of the extent of disease will be performed at the time of cystoscopy on day -14 and day 85 for 
patients within the main study. Disease response is not assessed at day 50 for applicable participants having resection 
of a second lesion. Data will also be collected during the follow-up from routine cystoscopy assessments.   
Baseline evaluations 
The location, size and morphology of all lesions prior to resection including identification of the marker lesion should 
be documented in a bladder diagram with photographs where possible at the time of the initial TURBT (day -14).  For 
patients who have consented to undergo a second TURBT the second non-marker lesion should be identified on the 
bladder diagram.   
Evaluations at end of treatment 
Repeat cystoscopy will be performed at the end of treatment on day 85.  The location, size and morphology of the 
marker lesion and any new or recurrent lesions should be documented in a bladder diagram with photographs where 
possible.  Transurethral resection will be performed for the marker lesion if persistent and any new or recurrent 
lesions at this time.  If the marker lesion is not visible, biopsies of the tumour bed will be performed.     
11.2 Tumour response 
Tumour response will be classified as follows:  
 
Pathological complete response: Clinical resolution of the marker lesion at day 85 with no pathological evidence of 
malignancy on biopsies of the tumour bed 
 
Clinical complete response: Clinical resolution of the marker lesion at day 85 without negative biopsies of the tumour 
bed. 
 
Non-response: Persistence of the marker lesion 
 
Progression: Development of any of the following 
 
T1 disease (lamina propria invasion) 
 
> T2 disease (muscle invasive) 
 
Lymph node(N1+) or distant metastases (M1) 
 
High grade (G3) disease or CIS 
 
Recurrence:  Appearance of one or more new lesions 
 


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Tumour response should be classified as ‘non evaluable’ (NE), only when it is not possible to classify it under another 
response category e.g. when baseline and/or follow-up assessment is either not performed or not performed 
appropriately.  
11.3 Other definitions of outcome: 
Toxic death:  
 
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
 
Death during the first three weeks of treatment that is not a toxic death. 
 
12 SAFETY REPORTING 
The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis 
throughout the study. Adverse event monitoring starts on the day of the TURBT procedure (Day -14) until 90 days post 
treatment, or 30 days following administration of the last dose of study medication if the subject initiates a new 
anticancer therapy. Should an Investigator become aware of any study drug related SAEs following this period these 
must also be reported as stated below.    All reportable AEs will be followed to a satisfactory conclusion during the 
treatment period. Any reportable drug-related AEs that are unresolved at the end of treatment visit are to be 
followed up by the Investigator until resolution or stabilisation. SAEs that are considered to be definitely unrelated to 
the trial intervention will not be followed up and monitored beyond the end of treatment. 
 
All AEs reported to the Trial Office will be processed according to internal SOPs. The Trial Office may request 
additional information for any AE as judged necessary. 
12.1 Adverse Event Definitions 
An Adverse Event or Experience (AE) is any untoward medical occurrence in a study subject temporally associated 
with the administration of an investigational medicinal product (IMP) or a comparator product, whether or not 
considered related to the IMP or a comparator product. An AE can therefore be any unfavourable and unintended 
sign, symptom, disease (new or exacerbated) and/or significant abnormal laboratory or physiological observation 
temporally associated with the use of a medicinal product.   
 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
 
 Results in death 
 
 
 Is life-threatening  
This refers to an event in which the subject was at risk of death at the 
time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
 Requires in-patient hospitalisation  
or prolongs existing inpatient 
hospitalisation  
 
In general, hospitalisation signifies that the subject has been admitted 
(usually involving at least an overnight stay) at the hospital or 
emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalisation are AEs.  If a 
complication prolongs hospitalisation or fulfils any other serious 
criteria, the event is serious.  When in doubt as to whether 
hospitalisation occurred or was necessary, the AE should be 
considered serious. 
 Results in persistent or significant 
incapacity or disability 
This means a substantial disruption of a person’s ability to conduct 
normal life functions.  It does not include experiences of relatively 
minor medical significance or accidental trauma (e.g. sprained ankle), 
which do not constitute a substantial disruption. 
 Is a congenital anomaly or birth 
defect 
 
 Is any other medically other 
Defined as an event that may jeopardise the patient or may require 


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medically important event 
intervention to prevent one of the outcomes listed above. Any new 
primary cancer must be reported as an SAE. 
 
 
An Adverse Drug Reaction (ADR) is an AE which is considered to be causally related to any dose of the IMP.  This 
means that a causal relationship between the IMP and the AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not consistent with 
applicable product information (referring to information in SPC or IB). 
 
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse drug reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an 
unapproved investigational product or SPC for an approved product). 
12.2 Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal assessments (e.g., 
ECGs, X-rays and scans) that are judged by the Investigator as clinically significant will be recorded as AEs or SAEs if 
they meet the definitions given above. By definition, all Grade 3 and or 4 laboratory abnormalities should be 
reported as SAEs. 
 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study 
or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs.  
However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with 
the disease being studied, unless judged by the Investigator as more severe than expected for the patient’s condition, 
or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.  
 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory 
finding or other abnormal assessment is clinically significant.  
12.3 Determining adverse event causality 
A Serious Adverse Reaction (SAR) is a SAE that may be related to trial treatment. The assessment of “relatedness” 
must be determined by a medically qualified individual and is primarily the responsibility of the PI at site or agreed 
designee. SAEs that will be considered related will include any SAE that is documented as possibly, probably or 
definitely related to protocol treatment. The assessment of relatedness is made using the following: 
 
 
The Investigator must endeavour to obtain sufficient information to confirm the causality of the adverse event (i.e. 
relation to surgery, study drug, background treatment, other illness, progressive malignancy etc.) and give their 
Classification 
Relationship 
Definition 
 Drug-related 
Definitely related 
 Starts within a time related to the study drug administration and 
 No obvious alternative medical explanation. 
Probably related 
 Starts within a time related to the study drug administration and 
 Cannot be reasonably explained by known characteristics of the 
patient’s clinical state. 
Possibly related 
1. Starts within a time related to the study drug administration and 
2. A causal relationship between the study drug and the adverse 
event is at least a reasonable possibility. 
Not drug-
related 
Probably not 
related 
3. The time association or the patient’s clinical state is such that the 
study drug is not likely to have had an association with the 
observed effect. 
Definitely not 
related 
 The AE is definitely not associated with the study drug 
administered. 
 


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opinion of the causal relationship between each AE and study drug.  This may require instituting supplementary 
investigations of significant AEs based on their clinical judgement of the likely causative factors and/or include seeking 
a further specialist opinion. 
12.4 Reference safety information (RSI) for assessment of expectedness 
The reference safety information (RSI) for the trial is section 7.1 of the Investigator Brochure for pembrolizumab 
which lists the expected side effects associated with the use of intravenous pembrolizumab. 
 
A copy of the current approved version of the IB must be held in the Site File for reference.  Any change or update to 
the IB during the trial will be made via substantial amendment.  
 
Local side effects of intravesical treatment 
Cystitis and haematuria are the most common local side effects of current intravesical therapy and typically resolve 
within 48 hours after instillation.  Bladder spasm, urinary frequency or urgency and urinary retention may also occur.  
Haematuria frequently occurs with cystitis following intravesical treatment and may be related to the extent of the 
previous TURBT.  In rare instances, catheterisation and bladder irrigation of clots or cystoscopy may be required.  
Table 1 below lists the most common adverse reactions seen in the SWOG study 8795 using intravesical BCG or MMC. 
 
Adverse Event 
TICE BCG n = 222 
MMC n = 220 
All grades 
Grade > 3 
All grades 
Grade > 3 
Dysuria 
115 (52%) 
6 (3%) 
77 (35%) 
5 (2%) 
Urgency/Frequency 
112 (50%) 
5 (2%) 
63 (29%) 
7 (3%) 
Haematuria 
85 (38%) 
6 (3%) 
56 (25%) 
5 (2%) 
Flu-like symptoms 
54 (24%) 
1 (<1%) 
29 (13%) 
0 
Fever 
37 (17%) 
1 (<1%) 
7 (3%) 
0 
Pain (not specified) 
37 (17%) 
4 (2%) 
22 (10%) 
1 (<1%) 
Haemorrhagic cystitis 
19 (9%) 
3 (1%) 
10 (5%) 
0 
Chills 
19 (9%) 
0 
2 (1%) 
0 
Bladder cramps 
18 (8%) 
0 
9 (4%) 
0 
Nausea 
16 (7%) 
0 
12 (5%) 
0 
Incontinence 
8 (4%) 
0 
3 (1%) 
0 
Myalgia/arthralgia 
7 (3%) 
0 
0 
0 
Diaphoresis 
7 (3%) 
0 
1 (<1%) 
0 
Rash 
6 (3%) 
1 (<1%) 
16 (7%) 
2 (1%) 
Table 1.  Adverse events seen in SWOG study 8795 associated with use of intravesical BCG or MMC 
12.5 Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
All SUSARS must be reported to the responsible Authority and main REC by the Trial Office within the required 
timelines: 
 
Fatal or life threatening SUSARs will be reported within 7 days of the Trial Office receiving the initial report. 
Any additional information will be reported within eight days of sending the first report. 
 
All other SUSARs will be reported within 15 days of the Trial Office receiving the initial report 
In addition, other safety issues qualify for expedited reporting where they might materially alter the current risk 
assessment of an IMP or be sufficient to change IMP administration or the overall conduct of the trial.  
12.6 Expedited reporting of SAEs 
The following SAE reporting requirements apply regardless of the Investigator’s assessment of the causality or 
expectedness of the SAE.  All SAEs should be reported on the trial SAE report form (see SAE report form and 
completion guidelines). 
 
If a Serious Adverse Event occurs that requires reporting, a Serious Adverse Event reporting form should be completed 
and emailed within 24 hours of becoming aware of the event to: 
 


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Pharmacovigilance Office, OCTO 
Email: octo-safety@oncology.ox.ac.uk  
Tel no:  +44 (0) 01865 227182 
 
OCTO will ensure SAEs are forwarded to MSD Global Safety within 2 working days of learning of the information.  If 
the SAE has not been reported to OCTO within the specified timeframe, a reason for lateness must be provided when 
sending the SAE Report Form. 
 
Investigators should also adhere to their local Trust policy for incident and SAE reporting in research. 
 
12.6.1 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be 
reported within 24 hours to the Trial Office as an Event of Clinical Interest on an SAE Form. OCTO will ensure ECIs are 
forward to the MSD Global Safety within the correct timeframe.   ECIs will be reported from the day of the TUBRT 
procedure (Day -14)  through to 90 days following cessation of study treatment, or 30 days following cessation of 
treatment if the subject initiates a new anti-cancer therapy. 
 
Events of clinical interest for this trial include:  
1. An overdose of MSD product, as defined in Section 8.6  
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 
aetiology.  
12.7 Follow-up of Serious Adverse Events 
A follow-up report must be completed when the SAE resolves, is unlikely to change, or when additional information 
becomes available. If the SAE is a suspected SUSAR then follow up information must be provided as requested by the 
Trial Office. 
 
If new or amended information on a reported SAE becomes available, the Investigator should report this on a new SAE 
form using the completion guidelines.  If using the original form to notify further information, you must initial and 
date all new or amended information so that all changes are clearly identified.  
 
SAEs that are considered to be definitely unrelated to the trial intervention will not be followed up and monitored 
beyond the end of treatment. 
12.8 Reporting Adverse Events on the CRF 
All AEs, including Serious AEs must be recorded on the case report forms (CRF) for that patient (unless otherwise 
specified in section 12.9. The information provided will include date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course, duration and outcome and relationship of the AE to study drug.  Any 
concomitant medications or any other therapy used to treat the event must be listed. The Investigator will provide an 
“other” cause for serious AEs considered to be unrelated to the study drug.  Sites should ensure data entered into the 
CRF is consistent with the SAE report information where applicable. 
 
Each separate AE episode must be recorded.  For example, if an AE resolves completely or resolves to baseline and 
then recurs or worsens again, this must be recorded as a separate AE. For AEs to be considered intermittent, the 
events must be of similar nature and severity. 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from study personnel or 
revealed by observation, physical examination, or other diagnostic procedures. Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE. 


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Terms and Grading of Events 
All adverse events and toxicities must be graded according to the NCI Common Terminology Criteria for adverse 
events (NCI-CTCAE) Version 4.03.   
12.9 Events exempt from being reported as AE/ SAEs 
Progression of underlying disease 
Disease recurrence and progression are efficacy endpoints for this study and will be captured on the CRF.  Adverse 
events including hospitalisation that are clearly consistent with disease recurrence or progression will not be reported 
as individual AE/SAEs.  Clinical symptoms of recurrence or progression will only be reported as adverse events if the 
symptom cannot be determined as exclusively due to the underlying malignancy, or does not fit the expected pattern 
of progression for the disease under study.  Every effort should be made to document the objective recurrence or 
progression of underlying malignancy.   
Death on study 
A death due to the disease under study is to be recorded on the Death CRF form. All other deaths must be reported as 
SAEs. 
 
Elective admissions and supportive care 
Elective admissions to hospital for patient convenience or for planned procedures or investigations or treatment as 
specified in this protocol and standard supportive care are not SAEs, and do not require SAE reporting.   
Expected toxicity of standard treatment 
The following adverse events related to surgery are considered expected if grade < 3 and are exempt from expedited 
reporting but should be reported using the appropriate CRF: 
 
Bladder discomfort or pain 
 
Urinary frequency 
 
Haematuria 
 
Urinary retention requiring catheterisation 
 
Infection of the bladder requiring antibiotics 
 
Delayed bleeding requiring removal of clots or further surgery 
 
Damage to the ureters requiring additional therapy 
 
Injury to the urethra causing delayed scar formation 
 
Perforation of the bladder requiring a temporary urinary catheter or open surgical repair 
12.10 Informing Investigators of new safety information 
The Trial Office or the Chief Investigator will ensure that all Investigators are kept informed in a timely manner, as new 
safety profile information becomes available. Investigators are responsible for briefing their study team and onward 
transmission to their R&D office as appropriate. 
 
13 PREGNANCY  
Pregnancies (in a participant or partner) occurring during treatment or within 120 days of last dose of pembrolizumab 
must be reported within 24 hours of becoming aware of it using the Pregnancy Notification Form. The Investigator 
must ensure that all patients are aware at the start of a clinical trial of the importance of reporting all pregnancies (in 
themselves and their partners) that occur during this period. 
Women who become pregnant should be withdrawn from treatment immediately.  
All reported pregnancies should be followed up through the participants General Practitioner or their Consultant 
Oncology until the outcome is known, additional consent for partners of trial patients will be sought to do this using 
the Pregnancy Information Sheet and Consent Form. Pregnancy outcome must be recorded in the medical record and 
in the follow-up section of the Pregnancy Notification Form.  If the outcome of the pregnancy meets any of the criteria 
for seriousness, it must also be reported as an SAE.  Examples of pregnancy outcomes that are SAEs include reports of: 
 
congenital anomalies or developmental delay, in the foetus or the child. 


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 
foetal death and spontaneous abortion.      
 
suspected adverse reactions in the neonate that are classified as serious 
 
14 DEFINING THE END OF TRIAL  
For this study the end of the trial is defined as “The last visit of the last patient undergoing the trial (LPLV) and up to 
24 months for follow-up”.  
The study will be stopped when: 
 
The stated number of patients to be recruited is reached. 
 
The stated primary and secondary objectives of the study are achieved.  
The sponsor and the Chief Investigator reserve the right to terminate the study earlier at any time. In terminating the 
study, they must ensure that adequate consideration is given to the protection of the participants’ best interests. 
 
15 STATISTICAL CONSIDERATIONS   
15.1 Sample size and power 
The primary aim of this study is safety, tolerability and toxicity and therefore the sample size has been chosen to give 
reasonable information on these endpoints.  In considering the secondary endpoint of response, using Ahern’s single 
stage phase II design with significance level 0.05 (one sided), power 0.8, we have set 20% as the highest level of 
efficacy at which we would not continue to another trial.  Based upon existing intravesical therapies a complete 
response rate of 55% may be achievable.  The 20% threshold requires a minimum of 13 patients in each arm of the 
trial, and if there are 6 successes in an arm then a 55% complete response rate is plausible.  Thirty patients will be 
randomised in total, to allow for drop out - No adjustment will be made for the multiple testing caused by having two 
arms.   
 
16 STATISTICAL ANALYSIS PLAN 
A detailed statistical analysis plan will be available from the time the first patient is recruited and will be finalised 
before any analysis is undertaken.  The analysis plan will be written in accordance with current Standard Operating 
Procedures and will be finalised and agreed by the trial statistician, a second statistician and the CI. 
 
The data from the safety run-in phase will be described including the variables that define the DLTs and the safety and 
toxicity variables.  
 
All analyses in the main trial will be on a modified intention-to-treat basis.  This means that patients will be analysed 
as they are randomised irrespective of the treatment actually received.  The intention-to-treat population will include 
all patients who have given their informed consent and for whom there is confirmation of successful allocation of a 
randomisation number.  This will be modified by omitting patients without the endpoint/outcome measure.  
 
It is therefore important that every effort is made to encourage patients, including those patients who do not 
receive/complete their allocated treatment, to attend for follow-up clinic visits to avoid bias in the analysis of the 
results. 
 
For the main trial, baseline characteristics will be summarised (number and frequency) for all patients by 
randomisation group.  Serious adverse events and adverse events will be summarised.  Complete response rate will be 
given for each treatment with a 90% confidence interval (CI). Kaplan‐Meier curves for the recurrence-free interval 
(RFI) and for progression-free interval (PFI) will be presented for each treatment group, with RFI and PFI estimates 
given at 6 months, 12 months, 18 months, and 2 years along with 90% CI. 


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16.1 Inclusion in analysis 
All patients will be included in the safety analysis.  All randomized patients with outcome data will be included 
in all analysis (modified intention to treat).  Full details of patients groups for analysis will be detailed in the 
separate Statistical Analysis Plan. 
16.2 Subgroup analysis 
No patient subgroup analysis is planned. 
16.3 Interim Analyses 
Interim analysis will be carried out for dose escalation as described in section 2.  
16.4 Procedures for reporting any deviation(s) from the original statistical plan 
Any deviations from the Statistical Analysis Plan will be noted in the final statistical report.  
16.5 Final analysis 
Based upon projected accrual rates, this trial is expected to complete recruitment within 24 months of opening to 
recruitment.  Final analysis will be after all patients have been followed up for at least 24 months with a publication 
planned within a year.  
17 TRIAL COMMITTEES 
17.1 Trial Management Group (TMG) 
The Chief Investigator will chair a TMG responsible for overseeing the successful conduct and publication of the trial.  
The TMG will review safety and dose escalations.  It will provide regular progress reports as required by the applicable 
steering committees and governance bodies.  
 
MSD will be informed of the outcome of any TMG meetings and the MSD Medical Advisor will be involved in end-of-
study discussions.  
17.2 Data and Safety Monitoring 
There is no Data and Safety Monitoring Committee (DSMC). SAEs upon receipt are reviewed by an independent 
nominated clinician as part of the trial office SAE Standard Operating Procedure.  Cumulative reports of all AEs & SAEs 
are reviewed by the TMG and an Independent Trial Steering Committee (IEPTOC) will be in place to monitor the safety 
of the trial on an ongoing basis (IEPTOC meets, on average, 6-monthly).  
17.3 Trial Steering Committee 
As an early phase study in the OCTO portfolio, the Independent Early Phase Trials Oversight Committee (IEPTOC) will 
provide overall supervision of the safe and effective conduct of the trial according to its terms of reference.  At least 
annually it will review trial progress against agreed milestones, adherence to protocol, patient safety and consider 
new information.  The IEPTOC has the authority to recommend study closure where appropriate.  
18 DATA MANAGEMENT 
18.1 Database considerations 
Data management will be performed via a web-based, bespoke trial database (OpenClinica). OpenClinica is a 
dedicated and validated clinical trials database designed for electronic data capture. See: http://www.openclinica.org.   
The Trial Office will provide sites with instructions and a video link for training purposes.  
 
The participants will be identified by a unique trial specific number and/or code in any database.  The name and any 
other identifying detail will NOT be included in any trial data electronic file. 
18.2 Case reports forms (CRFs) 
The Investigator and study site staff will ensure that data collected on each subject is recorded in the CRF as 


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accurately and completely as possible.   All appropriate laboratory data, summary reports and Investigator 
observations will be transcribed into the CRFs from the relevant source data held in the site medical record(s). CRFs 
entries will not contain any source data (unless otherwise specified in the completion instructions provided by the 
Trial Office). It is important to ensure that: 
 
the relevant CRFs are completed. 
 
all CRF data are verifiable in the source documentation or the discrepancies must be explained.  
 
CRF sections are completed in a timely fashion, as close to the visit or event being recorded as possible. 
 
data queries are resolved and documented by authorised study staff in a timely fashion. The reason for the 
change or correction should be given where appropriate. 
 
as much data as possible is entered and cleaned in preparation for each study database lock point. 
Note: ‘in a timely fashion’ means within no more than 14 working days of the initial event and within 28 days of 
receipt of a data query unless otherwise specified.  
The above considerations also apply to patients who are withdrawn early. If a patient withdraws from the study, the 
reason must be noted on the appropriate form and the patient must be followed-up as per protocol.  
18.3 Accounting for missing, unused, or spurious data. 
Attempts will be made to find any missing data and supplement this where possible after consultation with the 
Investigator.  The completeness and correctness of the data will be monitored as per the monitoring plan.  During the 
review of CRF’s by the trial statistician a check of the expected use of all data is made. 
 
19 CLINICAL STUDY REPORT  
All clinical data will be presented at the end of the study as data listings.  These will be checked to confirm the lists 
accurately represents the data collected during the course of the study.  The trial data will then be locked and a final 
data listing produced. The clinical study report will be based on the final data listings.  The locked trial data may then 
be used for analysis and publication.  
 
20 STUDY SITE MANAGEMENT 
20.1 Study site responsibilities 
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for conduct of the study, 
but may delegate responsibility where appropriate to suitably experienced and trained members of the study site 
team.  All members of the study site team must complete the Staff Contact Responsibility Sheet provided prior to 
undertaking any study duties.  The PI must counter sign and date each entry in a timely manner, authorising staff to 
take on the delegated responsibilities.  
20.2 Study site set up and activation 
The Principal Investigator leading the investigational study site is responsible for providing all required core 
documentation.  Mandatory Site Training organised by the Trial Office must be completed before the site can be 
activated.  The Trial Office will check to confirm that the site has all the required study information/documentation 
and is ready to recruit.  The site will then be notified once they are activated on the trial database and able to enter 
patients. 
20.3 Study documentation 
The Trial Office will provide an Investigator File and Pharmacy File to each investigational site containing the 
documents needed to initiate and conduct the study.  The Trial Office must review and approve any local changes 
made to any study documentation including patient information and consent forms prior to use. Additional 
documentation generated during the course of the trial, including relevant communications must be retained in the 
site files as necessary to reconstruct the conduct of the trial. 
 


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21 REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with the UK Clinical Trials 
Regulations1 and the applicable policies of the sponsoring organisation. Together, these implement the ethical 
principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an investigational 
medicinal product under the European Union Clinical Trials Directive. 
21.1 Ethical conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be presented to potential 
trial patients (e.g. advertisements or information that supports or supplements the informed consent) will be 
submitted to an appropriate Research Ethics Committee (REC), HRA (where required), regulatory authorities (MHRA), 
and host insitutions (s) for written approval. Principal Investigators will be approved by the REC. 
 
21.2 Regulatory Authority approval 
This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency (MHRA) Clinical Trials 
Authorisation (CTA). Approval to conduct the study will be obtained from the Responsible Authority prior to initiating 
the study.  
21.3 NHS Research Governance 
Investigators are responsible for ensuring they obtain local Trust management agreement to conduct the trial in 
accordance with local arrangements and policies. 
21.4 Protocol amendments 
Amendments are changes made to the research following initial approval. A ‘substantial amendment’ is an 
amendment to the terms of the Responsible Authority application (if applicable), the REC application, or to the 
protocol or any other supporting documentation, that is likely to affect to a significant degree: 
 
the safety or physical or mental integrity of the subjects of the trial; 
 
the scientific value of the trial; 
 
the conduct or management of the trial; or 
 
the quality or safety of the investigational medicinal product(s) used in the trial. 
 
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative aspects of 
the study. 
 
All amendments will be generated and managed according to the Trial Office standard operating procedures to ensure 
compliance with applicable regulation and other requirements.  Written approval will be obtained, where necessary, 
from the Research Ethics Committee (REC), HRA, regulatory authorities (MHRA), and host insitutions (s) for all 
amendments to the original approved documents. 
 
Written confirmation of all applicable REC, HRA, regulatory and local approvals must be in place prior to 
implementation by Investigators.  The only exceptions are for changes necessary to eliminate an immediate hazard to 
study patients (see below). 
 
It is the Investigator’s responsibility to update patients (or their authorised representatives, if applicable) whenever 
new information (in nature or severity) becomes available that might affect the patient’s willingness to continue in the 
trial.  The Investigator must ensure this is documented in the patient’s medical notes and the patient is re-consented if 
appropriate. 
21.5 Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures to protect trial participants from any 
immediate hazard to their health or safety. Urgent safety measures may be taken without prior authorisation. The 
                                                                    
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 


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trial may continue with the urgent safety measures in place. The Investigator must inform the Trial Office 
IMMEDIATELY if the study site initiates an urgent safety measure: 
 
The notification must include: 
 
Date of the urgent safety measure; 
 
Who took the decision; and 
 
Why the action was taken. 
 
The Investigator will provide any other information that may be required to enable the Trial Office to report and 
manage the urgent safety measure in accordance with the current regulatory and ethical requirements for expedited 
reporting and close out. The Trial office will follow written procedures to implement the changes accordingly.    
21.6 Temporary halt 
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short periods for 
administrative reasons or to declare a temporary halt. A temporary halt is defined a formal decision to: 
 
interrupt the treatment of subjects already in the trial for safety reasons; 
 
stop recruitment on safety grounds; or 
 
stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, including 
possible impact on the feasibility of completing the trial in a timely manner. 
 
The Trial Office will report the temporary halt via an expedited substantial amendment procedure. The trial may not 
restart after a temporary halt until a further substantial amendment to re-open is in place. If it is decided not to 
restart the trial this will be reported as an early termination. 
21.7 Serious Breaches 
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious breaches" to the 
MHRA within 7 days of the sponsor becoming aware of the breach. A serious breach is defined as “A breach of GCP or 
the trial protocol 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” 
 
Investigators must notify the Trials Office within one working day if any serious breach of GCP is suspected.  The Trial 
Office will review the event and, if appropriate will report a serious breach to the REC, Regulatory Authority and the 
NHS host organisation within 7 days of the Trial Office becoming aware of the breach. 
21.8 Trial Reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor 
reporting requirements.  
 
The Trial Office will determine which reports need to be circulated to Principal Investigators and other interested 
parties. Study sites are responsible for forwarding trial reports they receive to their local Trust as required. 
 
22 EXPENSES AND BENEFITS 
Study sites will provide expenses to patients as per local practice. 
 
23 QUALITY ASSURANCE 
23.1 Risk assessment  
A risk assessment and a monitoring plan will be prepared before the study opens and will be reviewed throughout the 
study if necessary in the light of significant changes while the study is ongoing or in response to outcomes from 
monitoring activities.  Monitoring plans will be amended as appropriate. 


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23.2 Monitoring 
Regular monitoring will be performed according to the monitoring plan. Data will be evaluated for compliance with 
the protocol, completeness and accuracy. The Investigator and institutions involved in the study will permit study-
related monitoring and provide direct on-site access to all study records and facilities if required. They will provide 
adequate time and space for the completion of monitoring activities. 
 
Study sites will be monitored centrally by checking incoming data for compliance with the protocol, consistency, 
completeness and timing.  The case report data will be validated using appropriate set criteria, range and verification 
checks.  The study site must resolve all data queries in a timely manner.   All queries relating to key outcome and 
safety data and any requiring further clarification will be referred back to the study site for resolution. For other non-
critical data items, OCTO staff may resolve data queries centrally providing the correct answer is clear. Such changes 
will be clearly identified in the CRF and the study site informed. 
 
Study sites will also be monitored remotely and/or by site visit as necessary to ensure their proper conduct of the 
trial.  OCTO staff will be in regular contact with site personnel to check on progress and deal with any queries that 
they may have. Monitoring reports will be sent to the site in a timely fashion.  The Investigator is expected to action 
any points highlighted through monitoring and must ensure that corrective and preventative measures are put into 
place as necessary to achieve satisfactory compliance. 
23.3 Audit and Regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure compliance 
with the protocol, GCP requirements and other applicable regulation or standards. It may also be subject to a 
regulatory inspection. Such audits or inspections may occur at any time during or after the completion of the study. 
Investigators and their host Institution(s) should understand that it is necessary to allow auditors/inspectors direct 
access to all relevant documents, study facilities and to allocate their time and the time of their staff to facilitate the 
audit or inspection visit. Anyone receiving notification of a Regulatory Inspection that will (or is likely to) involve this 
trial must inform the Trial Office without delay. 
 
24 RECORDS RETENTION & ARCHIVING 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate records to enable 
the conduct of a clinical trial and the quality of the research data to be evaluated and verified.  All essential 
documents must be stored in such a way that ensures that they are readily available, upon request for the minimum 
period required by national legislation or for longer if needed.  The medical files of trial subjects must be retained in 
accordance with applicable national legislation and the host institution policy. 
 
Retention and storage of laboratory records for clinical trial samples must also follow these guidelines.  Retention and 
storage of central laboratory records supporting PD endpoints and the disposition of samples donated via the trial 
must also comply with applicable legislation and Sponsor requirements. 
 
It is the University of Oxford’s policy to store data for a minimum of 5 years. Investigators may not archive or destroy 
study essential documents or samples without written instruction from the Trial Office. 
 
25 PATIENT CONFIDENTIALITY 
Personal data recorded on all documents will be regarded as confidential, and to preserve each patient’s anonymity, 
only their initials and date of birth will be recorded on the CRFs.  
 
The Investigator site must maintain the patient’s anonymity in all communications and reports related to the research. 
The Investigator site team must keep a separate log of enrolled patients’ personal identification details as necessary 
to enable them to be tracked. These documents must be retained securely, in strict confidence. They form part of the 
Investigator Site File and are not to be released externally. 
 


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26 STUDY FUNDING 
This trial is being run by the Oncology Clinical Trials Office (OCTO) at the University of Oxford and is being funded by 
the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme.  Any additional NHS clinical service support costs of patient care whilst 
on study should be met by the host study site.    
 
27 SPONSORSHIP AND INDEMNITY 
27.1 Sponsorship 
The Sponsor will provide written confirmation of Sponsorship and authorise the trial commencement once satisfied 
that all arrangements and approvals for the proper conduct of the trial are in place. A separate study delegation 
agreement, setting out the responsibilities of the Chief Investigator and Sponsor will be put in place between the 
parties.  
27.2 Indemnity 
The University has a specialist insurance policy in place which would operate in the event of any participant suffering 
harm as a result of their involvement in the research (Newline Underwriting Management Ltd, at Lloyd’s of London).  
NHS indemnity operates in respect of the clinical treatment that is provided. 
27.3 Contracts/Agreements 
This trial is subject to the Sponsor’s policy requiring that written contracts/agreements are agreed formally by the 
participating bodies as appropriate.  A Clinical Trial Agreement (CTA) will be placed between the Sponsor and 
participating organisations prior to site activation.   
 
The Sponsor will also set up written agreements with any other external third parties involved in the conduct of the 
trial as appropriate.  
 
28 PUBLICATION POLICY 
The Sponsor will retain ownership of all data arising from this trial. The intention is to publish this research in a 
specialist peer reviewed scientific journal on completion of the study. The results may also be presented at scientific 
meetings and/or used for a thesis. The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, 
press releases and any other publications arising from the trial and retain final editorial control. All 
publications/presentations should be shared with MSD prior to any presentations/submissions, allowing time for 
review (ideally 2 weeks for abstracts or posters and 4 weeks for manuscripts).  Authors will acknowledge the study 
sponsor and funding bodies as appropriate. 
 
29 REFERENCES 
 
1. 
Cancer Research UK Bladder cancer statistics. http://www.cancerresearchuk.org/health-professional/cancer-
statistics/statistics-by-cancer-type/bladder-cancer, Accessed June 2015. 
 
2. 
Kirkali, Z. et al. Bladder cancer: Epidemiology, staging and grading, and diagnosis. Urology 66, 4–34 (2005). 
 
3. 
Treatment of non-muscle invasive bladder cancer. uptodate.com at 
<http://www.uptodate.com/contents/treatment-of-non-muscle-invasive-bladder-
cancer?source=see_link&sectionName=RISK+STRATIFICATION&anchor=H10#H10>, Accessed June 2015 
 
4. 
Sylvester, R. J., Oosterlinck, W. & van der Meijden, A. P. M. A single immediate postoperative instillation of 
chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of 
published results of randomized clinical trials. The Journal of Urology 171, 2186–90 (2004). 


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5. 
Babjuk, M. et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. 
Eur. Urol. 64, 639–653 (2013). 
 
6. 
Sylvester, R. J. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder 
cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 49, 
466– 477 (2006). 
 
7. 
Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial 
bladder tumors. The Journal of Urology 116, 180–183 (1976). 
 
8. 
Mitropoulos, D. N. Novel insights into the mechanism of action of intravesical immunomodulators. In Vivo 19, 
611–621 (2005). 
 
9. 
Taniguchi, K. et al. Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) 
for superficial bladder cancer. Clin. Exp. Immunol. 115, 131–135 (1999). 
 
10. 
Silvester, R. J., Van der Meijden, A. & Lamm, D. L. Intravesical bacillus Calmette-Guérin reduces the risk of 
progression in patients with superficial bladder cancer: a meta-analysis of the published results of …. (J Urol, 
2002). 
 
11. 
Patard, J.-J. et al. Intravesical Bacillus Calmette-Guerin Treatment Improves Patient Survival in T1G3 Bladder 
Tumours. Eur. Urol. 41, 635–642 (2002). 
 
12. 
Shelley, M. et al. Intravesical Bacillus Calmette‐Guérin in Ta and T1 bladder cancer. (John Wiley & Sons, Ltd, 
2000). doi:10.1002/14651858.CD001986 
 
13. 
Witjes, J. A. Management of BCG Failures in Superficial Bladder Cancer: A Review. Eur. Urol. 49, 790–797 
(2006). 
 
14. 
Disis, M. L. Immune regulation of cancer. J. Clin. Oncol. 28, 4531–4538 (2010). 
 
15. 
Bubenik, J., Perlmann, P., Helmstein, K. & Moberger, G. Immune response to urinary bladder tumours in man. 
International Journal of Cancer 5, 39–46 (1970). 
 
16. 
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder 
carcinoma. Nature 507, 315–322 (2014). 
 
17. 
Thompson, R. H. et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for patients with renal cell carcinoma. Clin Cancer Res 13, 1757–1761 (2007). 
 
18. 
Fukunaga, A. et al. CD8+ Tumor-Infiltrating Lymphocytes Together with CD4+ Tumor-Infiltrating Lymphocytes 
and Dendritic Cells Improve the Prognosis of Patients with Pancreatic Adenocarcinoma. Pancreas 28, e26 
(2004). 
 
19. 
Zhang, L. et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer. N Engl J Med 348, 
203–213 (2003). 
 
20. 
Faraj, S. F. et al. Assessment of Tumoral PD-L1 Expression and Intratumoral CD8+ T Cells in Urothelial 
Carcinoma. Urology 85, 703.e1–703.e6 (2015). 
 
21. 
Sharma, P. et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial 
carcinoma. Proc. Natl. Acad. Sci. U.S.A. 104, 3967–3972 (2007). 
 
22. 
Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and Its Ligands in Tolerance and Immunity. 
http://dx.doi.org/10.1146/annurev.immunol.26.021607.090331 26, 677–704 (2008). 
 


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23. 
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. 
Nature Medicine 8, 793–800 (2002). 
 
24. 
Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. U.S.A. 99, 12293–12297 (2002). 
 
25. 
Iwai, Y., Terawaki, S. & Honjo, T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor 
cells by enhanced recruitment of effector T cells. Int. Immunol. 17, 133–144 (2005). 
 
26. 
Nomi, T. et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed 
death-1 pathway in human pancreatic cancer. Clin Cancer Res 13, 2151–2157 (2007). 
 
27. 
Wong, R. M. et al. Programmed death-1 blockade enhances expansion and functional capacity of human 
melanoma antigen-specific CTLs. Int. Immunol. 19, 1223–1234 (2007). 
 
28. 
Blank, C. et al. Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro. 
International Journal of Cancer 119, 317–327 (2006). 
 
29. 
Hamid, O. et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. N Engl J Med 
369, 134–144 (2013). 
 
30. 
Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced 
melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014). 
 
31. 
Garon, E. B. et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J Med 
150419053123009 (2015). doi:10.1056/NEJMoa1501824 
 
32. 
Gettinger, S. N., Shepherd, F. A., Antonia, S. J. & Brahmer, J. R. First-line nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 (J Clin 
Oncol, 2014). 
 
33. 
Motzer, R. J. et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J. 
Clin. Oncol. 33, 1430–1437 (2015). 
 
34. 
Chow, L. Q. et al. LBA31A Phase 1B study of Pembrolizumab in patients with human papilloma virus positive 
and negative head and neck cancer. Ann Oncol 25, mdu438.32 (2014). 
 
35. 
Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. 
Nature 515, 558–562 (2014). 
 
36. 
Plimack, E. R., Gupta, S., Bellmunt, J., Berger, R., Montgomery, B., Gonzalez, E. J., et al. (2014). LBA23A Phase 
1B study of Pembrolizumab in patients with advanced urothelial tract cancer. Annals of Oncology, 25(suppl 4), 
mdu438.24. doi:10.1093/annonc/mdu438.24 
 
37. 
Hughes, O. D. et al. Targeting superficial bladder cancer by the intravesical administration of copper-67-
labeled anti-MUC1 mucin monoclonal antibody C595. JCO 18, 363–370 (2000). 
 
38. 
Crawford, E. D. Intravesical therapy for superficial cancer: need for more options. JCO 20, 3185–3186 (2002). 
 
39. 
Gofrit, O. N., Zorn, K. C., Shikanov, S. & Steinberg, G. D. Marker Lesion Experiments in Bladder Cancer—What 
Have We Learned? The Journal of Urology 183, 1678–1685 (2010). 
 
 
APPENDIX 1: ECOG PERFORMANCE SCALE 
 


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Activity Performance Description 
Score 
 
 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care.  Confined to bed or chair more than 50% of waking hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
 
4 
 
 
APPENDIX 2: EAU RISK CATEGORIES 
 
 
Risk Category 
Definition 
Low-risk tumours 
Primary, solitary, Ta, LG/G1, <3cm, no CIS 
Intermediate-risk tumours 
All cases between categories of low and high risk 
High-risk tumours 
Any of the following: 
 
T1 tumours 
 
HG/G3 tumours 
 
CIS 
 
Multiple and recurrent and large (>3cm) Ta,G1, G2 tumours 
(all these conditions must be present) 
 
Adapted from EAU guidelines5 
 
APPENDIX 3: EORTC RISK TABLES 
 
Factor 
Recurrence score 
Progression score 
Number of tumours 
1 
0 
0 
2 to 7 
3 
3 
> 8 
6 
3 
 
Tumour size 
< 3cm 
0 
0 
> 3cm 
3 
3 
 
Prior recurrence rate 
Primary 
0 
0 
< 1/year 
2 
2 
> 1/year 
4 
2 
 
T category 


PEMBLA 
Confidential 
 
PemBla_Protocol_V3.0_08Mar2018 
Page 53 of 53                                     Protocol Template V5.0_28Nov2014 
IRAS Project ID: 209428  PEMBLA - PEMBROLIZUMAB IN INTERMEDIATE RISK RECURRENT NON-MUSCLE INVASIVE BLADDER 
CANCER (NMIBC) 
Ta 
0 
0 
T1 
1 
4 
 
CIS 
No 
0 
0 
Yes 
1 
6 
 
Grade 
G1 
0 
0 
G2 
1 
0 
G3 
2 
5 
 
Total score 
0-17 
0-23 
 
Probability of recurrence and progression according to total score: 
 
Recurrence score 
Probability of recurrence at 1 year 
(%) (95% CI) 
Probability of recurrence at 5 years 
(%) (95% CI) 
0 
15 (10-19) 
31 (24-37) 
1-4 
24 (21-26) 
46 (42-49) 
5-9 
38 (35-41) 
62 (58-65) 
10-17 
61 (55-67) 
78 (73-84) 
 
Progression score 
Probability of progression at 1 year 
(%) (95% CI) 
Probability of progression at 5 years 
(%) (95% CI) 
0 
0.2 (0-0.7) 
0.8 (0-1.7) 
2-6 
1.0 (0.4-1.6) 
6 (5-8) 
7-13 
5 (4-7) 
17 (14-20) 
14-23 
17 (10-24) 
45 (35-55) 
 

SAP_001.pdf: 
 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 1 of 18 
 
 
 
A parallel group phase I/II marker lesion study to assess the 
safety, tolerability and efficacy of intravenous or intravesical 
Pembrolizumab in intermediate risk recurrent non-muscle 
invasive bladder cancer 
 
Statistical Analysis Plan 
Version 2.0 – 03Nov2017 
 
Based on Protocol version 2.0 – 28Jul2017 
Name 
Title 
Role 
(Author/Reviewer/Approver) 
Peter Dutton 
Medical 
Statistician 
Author, Approver 
Joanna 
Moschandreas 
Senior Medical 
Statistician 
Author, Approver 
Lucy Griffiths 
Trial Manager 
Reviewer 
Andrew Protheroe 
Chief Investigator 
Reviewer & Approver 
 
Oncology Clinical Trials Office (OCTO) 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine (CSM) 
 
                          
                     
 
 
 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 2 of 18 
 
Contents 
 
Introduction .................................................................................................................................... 3 
1.1 
Key personnel ..................................................................................................................................... 3 
 
Background Information .................................................................................................................. 4 
2.1 
Research Hypotheses and Study Objectives ...................................................................................... 4 
2.2 
Study Design and trial expected time-points ..................................................................................... 5 
2.3 
Eligibility ............................................................................................................................................. 6 
2.3.1 
Inclusion criteria ............................................................................................................................ 6 
2.3.2 
Exclusion criteria ............................................................................................................................ 7 
2.4 
Treatment Interventions .................................................................................................................... 8 
2.5 
Sample Size ........................................................................................................................................ 8 
2.6 
Randomisation ................................................................................................................................... 8 
2.7 
Outcomes Assessment Schedule ....................................................................................................... 9 
 
Quality Control and Data Validation ............................................................................................... 10 
 
Interim Analysis and Data Review .................................................................................................. 10 
 
Safety run-in decision process ........................................................................................................ 10 
5.1 
The planned safety run-in (Protocol Section 5.2) ............................................................................ 10 
5.2 
Replacement of patients .................................................................................................................. 11 
5.3 
TMG monitoring and monitoring triggers ........................................................................................ 12 
5.4 
TMG meeting ................................................................................................................................... 13 
5.5 
Data considered by the TMG ........................................................................................................... 13 
5.6 
TMG decisions .................................................................................................................................. 13 
 
Specification of Statistical Packages ................................................................................................ 13 
 
Descriptive Analyses ...................................................................................................................... 14 
7.1 
Representativeness of Study Sample and Patient Throughput ....................................................... 14 
7.2 
Baseline Characteristics ................................................................................................................... 14 
7.3 
Comparison of Losses to Follow-up ................................................................................................. 15 
7.4 
Description of Available Data ........................................................................................................... 15 
7.5 
Description of Compliance with Intervention .................................................................................. 15 
7.6 
Unblinding of Randomised Treatments ........................................................................................... 15 
7.7 
Reliability .......................................................................................................................................... 15 
 
Definition of populations for Analysis ............................................................................................. 15 
 
Analyses to address primary aims ................................................................................................... 16 
9.1 
Intravesical safety run-in .................................................................................................................. 16 
9.2 
Main study (Phase II trial) ................................................................................................................ 16 
9.3 
Pre-specified Subgroup Analysis ...................................................................................................... 16 
9.4 
Treatment by Centre Interaction ..................................................................................................... 16 
 Analysis to address secondary aims ................................................................................................ 16 
10.1 
Efficacy ............................................................................................................................................. 16 
10.2 
Recurrence and progression free interval ....................................................................................... 17 
 Additional Analyses ....................................................................................................................... 17 
 Appendix: Glossary of abbreviations .............................................................................................. 18 
 Changes from previous version of SAP ............................................................................................ 18 
 References ..................................................................................................................................... 18 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 3 of 18 
 
 
 
 Introduction 
This document details the proposed presentation and analysis for the main paper(s) reporting results from the 
parallel group phase I/II marker lesion study to assess the safety, tolerability and efficacy of intravenous or 
intravesical pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (PemBla), 
funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and Merck Sharp & Dohme.  The 
results reported in these papers should follow the strategy set out here.  Subsequent analyses of a more 
exploratory nature will not be bound by this strategy, though they are expected to follow the broad principles 
laid down here.  The principles are not intended to curtail exploratory analysis (for example, to decide cut-
points for categorisation of continuous variables), nor to prohibit accepted practices (for example, data 
transformation prior to analysis), but they are intended to establish the rules that will be followed, as closely 
as possible, when analysing and reporting the trial.  
The analysis strategy will be available on request when the principal papers are submitted for publication in a 
journal.  Suggestions for subsequent analyses by journal editors or referees, will be considered carefully, and 
carried out as far as possible in line with the principles of this analysis strategy; if reported, the source of the 
suggestion will be acknowledged. 
Any deviations from the statistical analysis plan will be described and justified in the final report of the trial.  
The analysis should be carried out by an identified, appropriately qualified and experienced statistician, who 
should ensure the integrity of the data during their processing.  Examples of such procedures include quality 
control and evaluation procedures. 
1.1 
Key personnel 
List of key people involved in the drafting and reviewing this SAP, together with their role in the trial and their 
contact details. 
Trial statisticians 
Mr Peter Dutton 
Medical Statistician 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford.  OX3 7LD 
Email:  peter.dutton@csm.ox.ac.uk 
 
Dr Joanna Moschandreas 
Senior Medical Statistician 
Centre for Statistics in Medicine 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford.  OX3 7LD 
Email:  joanna.moschandreas@csm.ox.ac.uk 
 
Trial Manager 
Mrs Lucy Griffiths 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 4 of 18 
 
Oncology Clinical Trials Office (OCTO) 
Department of Oncology, The University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ, UK 
Tel: +44 (0)1865 227190 or 617013 
Email: octo-pembla@oncology.ox.ac.uk 
 
 
Chief Investigator 
Dr Andrew Protheroe 
Department of Oncology 
Oxford Cancer and Haematology Centre 
Churchill Hospital 
Oxford University Hospitals NHS Trust 
Old Road, Oxford.  OX3 7LJ 
Tel: +44 (0)1865 572300 
Email: andrew.protheroe@oncology.ox.ac.uk 
 
 
 Background Information 
This trial will evaluate the safety and efficacy of intravenous and intravesical administration of 
Pembrolizumab, a PD-1 inhibitor, in the setting of recurrent intermediate risk bladder cancer. 
2.1 
Research Hypotheses and Study Objectives 
Primary Objective 
Endpoints/ Outcome measures 
 
To assess the safety, tolerability and toxicities of 
intravesical and intravenous pembrolizumab 
after TURBT in patients with intermediate risk 
NMBIC  
 Incidence and severity of adverse events (NCI 
CTCAE v4.03) 
Secondary Objectives 
Endpoints 
 To provide a preliminary assessment of efficacy 
of treatment with intravesical pembrolizumab in 
patients with intermediate risk NMIBC  
 Complete response rate of marker-lesion as 
assessed clinically at TURBT and confirmed on 
biopsy of tumour bed 
 Recurrence and progression free interval  
 To provide a preliminary assessment of efficacy 
of treatment with intravenous pembrolizumab in 
patients with intermediate risk NMIBC 
 Complete response rate of marker-lesion as 
assessed clinically at TURBT and confirmed on 
biopsy of tumour bed 
 Recurrence and progression free interval  
Tertiary/Exploratory Objectives 
Endpoints 
 
Determine correlation between expression of 
PD-L1, PD-L2 and PD-1+ infiltrating lymphocytes 
and efficacy of pembrolizumab therapy after 
TURBT in intermediate risk NMIBC patients 
 
Tumour/stromal cell PD-L1 and PD-L2 
expression and presence of PD-1+ infiltrating 
lymphocytes in pre and post treatment 
tumour samples measured by 
immunohistochemistry and FACS analysis  


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 5 of 18 
 
 
Definition of gene expression signatures and 
genetic profiles capable of predicting efficacy of 
pembrolizumab treatment in NMIBC patients. 
 
Gene expression profiling and DNA sequencing 
on pre-treatment blood and tumour samples  
 
To evaluate the effects of pembrolizumab 
treatment on the immunological profile and 
tumour specific immune responses in patients 
with intermediate risk NMIBC  
 
Identification of myeloid or T cell responses in 
the tumour microenvironment associated with 
response to treatment 
 
Analysis of TCR repertoire and clonality of 
infiltrating T cells in resected tumour 
specimens, urine and normal bladder tissue 
 
Analysis of TCR repertoire and clonality of 
PBMC before, during and after treatment 
 
Analysis of cytokines in blood and urine 
 
To investigate the pharmacokinetics of 
intravesical pembrolizumab 
 
Analysis of blood levels of pembrolizumab 
during treatment 
 
2.2 
Study Design and trial expected time-points 
The PemBla trial is a parallel group, open label, multi-centre, phase I/II marker-lesion study in recurrent 
intermediate risk NMIBC.  Thirty patients (fifteen in each of two arms) will be randomised 1:1 to treatment 
with either intravesical pembrolizumab (Arm A) or intravenous pembrolizumab (Arm B).  The main study will 
be preceded by a single institution safety run-in phase involving intra-patient dose escalation in six patients to 
confirm the safety and tolerability of intravesical pembrolizumab and the dose to be used in the randomised 
phase. The primary outcomes are safety, tolerability and toxicity.  
 
Date of grant activation: 
21Apr2017 (date contract between UOxford and Merck fully 
executed) 
Date of start of recruitment: 
 
 
Expected 01Aug2017 
Date expected end of recruitment: 
 
15Mar2019 
Date expected end follow-up: 
 
 
15Mar2021 
Date expected start of analysis:  
 
Final analysis expected spring/summer 2021 
Date end of grant: 
Grant is not date bound but paid in milestones, final payment 
will be upon verification of Final study results posted on 
Clinicaltrials.gov 
Target number of subjects: 
 
 
36 (6* + 15 per arm) 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 6 of 18 
 
Participating Centres: 
 
 
 
3 - Churchill, Royal Surrey and Southampton General 
*For phase I six evaluable patients are required so more patients may be recruited to fulfil this criteria. 
2.3 
Eligibility 
2.3.1 Inclusion criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial and comply with the protocol 
scheduled follow-up visits and examinations for the duration of the study 
2. Be  18 years of age on day of signing informed consent 
3. Have recurrent NMIBC for which adjuvant treatment post TURBT would be a reasonable treatment 
option 
4. Main study only: 
a. Have recurrent, multiple (minimum 2) tumours consistent with NMIBC  
b. Have at least one lesion of between 5-10mm in size clinically that can be left un-resected at 
TURBT as the marker lesion 
c. Have histologically confirmed low grade transitional cell NMIBC at original and any 
subsequent diagnosis 
5. Have a normal upper urinary tract (as evidenced by ultrasound or CT urography within 2 years prior 
to randomisation) and no evidence of tumour in prostatic urethra at flexible cystoscopy 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale 
7. Have adequate organ function as defined in the table below: 
 
8. Female subjects of childbearing potential should have a negative urine or serum pregnancy test at 
screening and within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required 
9. Both male and female subjects of childbearing potential (Section 5.1) must be willing to use an 
adequate method of contraception as outlined in section 5.1 for the course of the study and until 120 
days after the last dose of the study medication 
 
Lab Test 
Value required 
Haemoglobin (Hb) 
≥ 9 g/dL without transfusion or EPO dependency 
Absolute neutrophil count (ANC) 
≥ 1.5 x 109/L 
Platelet count 
≥ 100 x 109/L 
Total bilirubin  
≤ 1.5 times the upper limit of normal (ULN) or direct 
bilirubin < ULN for subjects with total bilirubin levels > 1.5 x 
ULN 
Serum alanine aminotransferase (ALT) 
and/or serum aspartate aminotransferase 
(AST) 
≤ 2.5 x ULN 
Serum creatinine OR 
Measured or calculated creatinine 
clearancea 
≤ 1.5 x ULN OR 
≥ 60ml/min for subject with creatinine levels > 1.5 x 
institutional ULN 
Albumin 
≥ 25g/L 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) and 
Activated Partial Thromboplastin Time 
(aPTT) 
≤ 1.5 x ULN unless subject is receiving anticoagulant therapy 
as long as PT or APTT is within therapeutic range of 
intended use of anticoagulants 
a Creatinine clearance should be calculated as per institutional standard 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 7 of 18 
 
2.3.2 Exclusion criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has received prior radiotherapy to the pelvis 
2. Has significant urinary incontinence or known bladder instability 
3. Main study only: 
a. Has more than 2 out of 3 of the following present at the current time: 
i. ≥ 8 tumours 
ii. Tumour ≥ 3cm in size 
iii. Frequent recurrence (> 1/year) 
b. Has a previous history of any of the following: T1 tumour, high grade/G3 tumour, carcinoma 
in situ, multiple recurrent large (> 3cm) Ta, G1 or G2 tumours.   
c. Had a primary tumour of unknown pathological stage or grade 
d. Has disease for which resection of all visible tumours is not possible 
4. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 28 days of 
the first dose of trial treatment 
5. 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.  Subjects requiring 
use of inhaled or intranasal corticosteroids or local steroid injections would not be excluded 
6. Has a known history of active TB 
7. Has received intravesical BCG treatment within 30 days prior to the first dose of trial treatment 
8. Has hypersensitivity to pembrolizumab or any of its excipients  
9. Has had treatment with any other anti-cancer monoclonal antibody within 28 days prior to 
enrolment or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier 
10. Has had treatment with prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks of administration of study drug or who has not recovered (i.e. ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent. 
11. Has a known additional malignancy that is progressing or requires active treatment.  Exceptions 
include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and 
any neurological symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for a t least 7 days prior to trial treatment.  This exception does 
not include carcinomatous meningitis which is excluded regardless of clinical stability 
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use 
of disease modifying agents or immunosuppressive drugs).  Replacement therapy (e.g. thyroxine, 
insulin or physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) 
is not considered a form of systemic treatment 
14. Has a known history of, or any evidence of active, non-infectious pneumonitis 
15. Has an active or intractable infection requiring systemic therapy 
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
Investigator 
17. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the 
requirements of the trial 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 8 of 18 
 
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration 
of the trial, starting with the pre-screening or screening visit through to 120 days after the last dose 
of trial treatment 
19. Has received prior therapy with an anti-PD-1, anti PD-L1, or anti-PD-L2 agent 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
21. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is 
detected) 
22. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
2.4 
Treatment Interventions 
Both experimental treatments arms will give Pembrolizumab. Arm A will be given by intravesical 
administration at a dose and schedule to be determined by the TMG following analysis of the safety run-in. 
Arm B will be by intravenous infusion at a dose of 200mg. See Figure 2.1 for details. 
 
Figure 2.1 Schedule of treatment administration for main study.  *TURBT for resection of second non-marker 
lesion in at least 5 patients in each arm.  Black arrows denote treatment administration 
 
2.5 
Sample Size 
The primary aim of this study is safety, tolerability and toxicity and therefore the sample size has been chosen 
to give reasonable information on these endpoints.  In considering the secondary endpoint of response, using 
A’Hern’s single stage phase II design with significance level 0.05 (one sided), power 0.8, we have set 20% as 
the highest level of efficacy at which we would not continue to another trial (A’Hern, 2001).  Based upon 
existing intravesical therapies a complete response rate of 55% may be achievable.  The 20% threshold 
requires a minimum of 13 patients in each arm of the trial, and if there are 6 successes in an arm then a 55% 
complete response rate is plausible.  Thirty patients will be randomised in total, to allow for drop out - No 
adjustment will be made for the multiple testing caused by having two arms.   
2.6 
Randomisation 
Randomisation will be 1:1 by minimisation, using site as a stratification variable. Patients will be assigned with 
a probability of 0.8 to the treatment that minimises the imbalance (Brown et al, 2005). 
Full details on the randomisation schedule are available in the Randomisation and Blinding Plan, stored in the 
confidential statistical section of the TMF. 
 
 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 9 of 18 
 
 
2.7 
Outcomes Assessment Schedule 
Visit Description 
Screening 
TURBT 
Pre-treatment 
On treatment 
TURBT 
End of 
treatment visit 
Follow-up 
Day 
-44 to 
-15 
-14 
-13 
to 1 
1 
 
8 
 
15 
 
22 
 
29 
 
36 
 
43 
 
50 
 
64 
 
85 
+/-7 
92§ 
+7 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Physical examination 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Vital signsa 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Blood for haem and biochemb 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Blood for TFTsc 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
Urinalysisd 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Pregnancy test 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Blood for germline DNAe 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood for immunoprofilingf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X+ 
X 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resection of bladder tumour(s) 
TURBT 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Tumour assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
Bladder barbotage 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Bladder biopsyg 
 
X 
 
 
 
 
 
 
 
 
X+ 
 
X* 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Urine for cytokinesh 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Research Blood **i  
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Administration of intravesical 
Pembrolizumab (Safety run-in 
and Arm A) j 
 
 
 
X 
 
X 
+/-1 
X 
+/-1 
X 
+/-1 
X 
+/-1 
X 
+/-1 
 
 
X* 
+/-1 
 
 
 
Administration of intravenous 
Pembrolizumab (Arm B) j 
 
 
 
X 
 
 
X 
+/-3 
 
 
X 
+/-3 
 
X 
+/-3 
 
 
 
Recurrence data (RFS and PFS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Optional  tumour sample at 
recurrence or progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Visits shaded in grey are only applicable to patients who are due for drug administration on that day 
* For patients in the main study only (not patients in safety-run in) 
** For patients receiving intravesical treatment only 
+ For patients who have consented to having second non-marker lesions resected only 
§ The end of study visit for patients in the safety run-in will be performed on day 64 
a Vital signs to include systolic / diastolic blood pressure, pulse rate, respiratory rate, oxygen saturations and temperature.  To be 
performed according to the vital signs scheduling details in section 8.3. 
b To include FBC, clotting screen, sodium, potassium, urea, creatinine, calcium, phosphate, total protein, albumin, bilirubin, ALP, AST 
and/or ALT 
c To include TSH, T3 and T4 
d To include Blood, White Cells, Protein, Nitrites, pH, culture and sensitivity 
e 10ml of blood in EDTA tube, taken pre-treatment 
f 50ml of blood in Na-Heparin tubes 
g Biopsy of normal bladder epithelium + tumour bed if complete response of marker lesion 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
Dohme Corp Investigator Studies Programme 
EudraCT: 2016-002267-33 
______________________________________          
SAP Version No: 2.0 
 
OCTRU-OST-001_V2.0_13Mar2015 
Date: 03Nov2017 
 
Effective Date 13Mar2015   
SAP Author: Peter Dutton  
Page 10 of 18 
 
h For patients receiving intravesical treatment, urine for cytokines will be collected pre-dose and post-dose (first post-treatment 
urine sample after the drug has been voided from the bladder) on day 1 and thereafter post-dose only.  For patients receiving 
intravenous treatment, urine for cytokines will be collected pre-dose only.  
i Blood for research  will be taken pre-dose and 2 hours post dose (counted from the completion of syringe/catheter administration 
of suspension into the bladder) for patients receiving intravesical treatments on day 1, and pre-dose only at cycle 6 (d36).  
j Trial treatment should begin 14 days after TURBT or as close as possible to this date. 
 Quality Control and Data Validation 
The PemBla Trial Office will monitor the compliance of study sites taking part in the trial on an ongoing basis. 
Where non-compliance with the protocol or the standard procedures set out in the Investigator Agreement is 
suspected, the Chief Investigator for the study will contact the study site to resolve any problems. If 
appropriate, the matter will be referred to the PemBla Trial Management Group at their next meeting or by 
correspondence with members if urgent. 
OCTO staff will be responsible for checking forms for compliance with the protocol, data consistency, missing 
data, timing and maintaining regular contact with site personnel to check on progress and deal with queries 
as they arise. 
Duplicate analysis of the response endpoint will be undertaken by a second statistician and this will be 
documented in the final statistical report. Any deviation in these analyses will be accounted for and corrections 
made. 
The primary outcome and key secondary outcomes will be analysed, following the analyses detailed in this 
SAP, by a second statistician independently using different statistical software (if possible).  Any discrepancies 
will be reported in the Statistical report (See OCTRU SOP STATS-005 Statistical Report).  
 Interim Analysis and Data Review  
There is no Data and Safety Monitoring Committee (DSMC). SAEs upon receipt are reviewed by an 
independent nominated clinician as part of the trial office SAE Standard Operating Procedure.  Cumulative 
reports of all AEs & SAEs are reviewed by the TMG and an Independent Trial Steering Committee (IEPTOC) will 
be in place to monitor the safety of the trial on an ongoing basis (IEPTOC meets, on average, 6-monthly). 
Section 5 details the monitoring and decision process which will oversee the safety run-in portion of the study. 
The TMG will be responsible for the day to day monitoring and steering the dosing of patients during this time. 
 Safety run-in decision process 
The TMG will be responsible for oversight, monitoring and decision making during the safety run-in portion 
of the study. This section details the triggers for a TMG meeting as well as the decisions available to the 
TMG. 
 
5.1 
The planned safety run-in (Protocol Section 5.2) 
The safety and tolerability of intravesical Pembrolizumab will be evaluated in six evaluable patients following 
TURBT for NMIBC prior to the main (phase 2) study commencing.  Treatment will be administered once weekly 
according to the following schedule.  Intra-patient dose escalation of intravesical Pembrolizumab will be 
performed in paired patient cohorts with the anticipated doses as shown below.    
 
 
 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
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Table 5-1 Planned dose escalation 
 
Cohort 
 
Patient 
Dose of Intravesical Pembrolizumab (mg) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
1 
1 
50 
50 
100 
100 
200 
200 
2 
50 
50 
100 
100 
200 
200 
2 
3 
100 
100 
200 
200 
200 
200 
4 
100 
100 
200 
200 
200 
200 
3 
5 
200 
200 
200 
200 
200 
200 
6 
200 
200 
200 
200 
200 
200 
 
Patients will be assessed for dose limiting toxicities (DLT) as well as for overall tolerability of the treatment.  A 
DLT is defined as a clinically significant, drug related, grade 4 haematological or > grade 3 non-haematological 
toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient.  
Treatment start dates will be staggered by at least one week between patients.  In addition, treatment of 
patients in cohort 2 and 3 will not commence until both patients in the preceding cohort have cleared the DLT 
period for the D15 dose. 
If more than 1 patient experiences a DLT at a certain dose, this dose will be declared non-tolerated and further 
escalation will cease.  Patients who have already commenced treatment at the same dose and are tolerating 
treatment may continue at this dose.  If a DLT occurs in either patient at the first dose of cohort 1, or in more 
than 1 patient at subsequent doses, the TMG will meet to consider the available safety data and determine 
how to proceed.  Recruitment of further patients to a cohort or investigation of intermediate doses or 
treatment intervals may be considered. 
Patients who do not receive at least 5 out of the 6 scheduled treatments, except for reasons of drug-related 
toxicity, will be replaced such that there are 6 patients evaluable for tolerability. Patients who are replaced in 
this manner are not evaluable. 
When considering the dose to take forward to the randomised part of the study the TMG will also consider 
the overall tolerability of the treatment.  Patients must be able to receive at least 5 out of the 6 treatments 
for the regime to be defined as tolerable.  
5.2 
Replacement of patients 
Six evaluable patients are required for the TMG to confirm the tolerated intravesical dose for the main study.  
Should a patient become unevaluable and need to be replaced, the patient should be replaced into the same 
cohort unless the next cohort has already been opened1 . For example, if patient 2 in cohort 1 does not receive 
the last two doses and Cohort 2 has already been decided by the TMG to be opened to recruitment, the 
                                                          
 
1 Treatment of patients in cohorts 2 & 3 can start once both patients in the preceding cohort have cleared the DLT 
period for the D15 dose. 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
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replacement patient can be assigned to start as one of the two patients in Cohort 2. To ensure 6 evaluable 
patients complete the safety period, a third patient would be recruited into Cohort 3.  
Cohorts will be considered complete when two patients have successfully received at least 5 doses. Patients 
who miss more than one dose, except for reasons of drug-related toxicity, will be replaced.  
Patients missing more than one dose due to drug-related toxicity will not be replaced2. 
5.3 
TMG monitoring and monitoring triggers 
Provided that a patient does not experience a DLT the treating investigator will be responsible for the day to 
day care of the patient including within patient dose escalations. i.e. Intra-patient dose escalation will be 
overseen and managed by site. No TMG safety review nor OCTO input will be required. Within patient dose 
escalation will not exceed the doses laid out in  
 
                                                          
 
2 Protocol 6.1 (page 26): “During the safety run in phase patients who do not receive at least 5 out of the 6 scheduled 
treatments, except for reasons of drug-related toxicity, will be replaced such that there are 6 patients evaluable for 
tolerability”. 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
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Table 5-1. 
 
Planned triggers: 
1. In the event of a DLT 
2. If it is not clear if a patient is evaluable 
3. To review safety data once 2 patients in a cohort have cleared the DLT period for the D15 dose (to 
make a decision regarding opening the next cohort)  
4. The TMG may also decide to review events that would meet DLT criteria except for not occurring 
within 7 days of administration of the first  treatment at a given dose for that patient 
5. Upon completion of the run in, to review all safety data prior to opening the main (phase II) study 
 
The TMG will meet if one of the planned triggers occurs. There may be cause for the TMG to meet to review 
the safety data for some other (unplanned) reason.  
 
5.4 
TMG meeting 
Upon a monitoring trigger occurring the following procedure will be followed: 
1. The Trial Manager (TM) will inform the TMG that a meeting is required following a triggered event, 
detailing the trigger for the meeting. A date for the meeting will be fixed. The meeting may take 
place in person, via T/C or via email discussion. 
2. The TM may arrange for a datalock to be sent to the statistical team prior to the meeting. 
3. The decisions made by the TMG at the meeting will be recorded in the minutes and will be circulated 
to all parties. 
 
5.5 
Data considered by the TMG 
The TMG will be provided with available safety data. The TMG may request further data to help make their 
decisions as informed as possible. 
5.6 
TMG decisions 
The TMG will review all the available data and will be responsible for making informed decisions aimed at 
finding a safe and tolerable dose while protecting the trial patients from toxic dose levels.  
 The TMG may make the following decisions during the safety run-in phase: 
1. Declare one or more doses toxic, preventing further patients receiving doses at or above this dose. 
Within patient dose escalation will cease at the highest dose not declared toxic. 
2. Determine the patient evaluability and replacement 
3. Recruit further patients to a cohort and/or investigate intermediate doses or treatment intervals. 
 
At the end of the safety run-in phase the TMG will meet to decide on the dose which will be taken forward 
to the randomised phase of the study for the intravesical arm. 
 
 Specification of Statistical Packages 
All analysis will be carried out using appropriate validated statistical software such as STATA, SAS or R statistical 
software. The relevant package and version number will be recorded in the Statistical report. 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
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 Descriptive Analyses 
7.1 
Representativeness of Study Sample and Patient Throughput 
 
Figure 7.1 Consort flow diagram 
A flow diagram of the safety run in will also be provided. 
7.2 
Baseline Characteristics 
Numbers (with percentages) for binary and categorical variables and means (and standard deviations), or 
medians (minimum, maximum) for continuous variables will be presented; there will be no tests of statistical 
significance nor confidence intervals for differences between randomised groups on any baseline variables. 
Table 7-1 Baseline characteristics 
 
 
Safety 
Cohort 1 
(n= ) 
Safety 
Cohort 2 
(n= ) 
Safety 
Cohort 3 
(n= ) 
Arm A (n= ) 
Arm B (n =  ) 
Age 
Mean (SD)1 
 
 
 
 
 
Gender 
Male 
 
 
 
 
 
Ethnicity 
… 
 
 
 
 
 
Smoking status 
Current 
 
 
 
 
 
 
Ex-smoker 
 
 
 
 
 
 
Never smoked 
 
 
 
 
 
Site of primary 
Tumour 
… 
 
 
 
 
 
Histology 
… 
 
 
 
 
 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
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Prior Surgery 
Yes 
 
 
 
 
 
Prior Chemo 
and/or 
intravesical 
treatment 
Yes 
 
 
 
 
 
Treating Centre 
Churchill 
 
 
 
 
 
 
Royal Surrey 
(Guildford) 
 
 
 
 
 
 
Southampton 
General 
 
 
 
 
 
1Or median (min, max) if not normally distributed. 
 
7.3 
Comparison of Losses to Follow-up 
Loss to follow-up together with reasons will be reported for each separate cohort in the intravesical safety 
run-in and by intervention arm in the randomised stage of the study. There will be no statistical comparison 
between arms. 
7.4 
Description of Available Data  
Missing data will be investigated and supplemented where possible. The completeness and correctness of the 
data will be monitored as per the monitoring plan. 
The number of patients with missing data will be presented by each dose level. The reason for missing data 
will be indicated e.g. loss to follow-up, consent withdrawn, removed from study due to serious adverse events, 
death. 
7.5 
Description of Compliance with Intervention 
The compliance with treatment will be reported by treatment group in a graphical and tabular format. Dose 
delays, omissions and reduction will be reported with reasons where available. 
7.6 
Unblinding of Randomised Treatments 
The study is unblinded and there is no direct comparison between treatment arms. For this reason all analysis 
will be unblinded. 
7.7 
Reliability 
Data derivation/manipulation will be checked to ensure validity of the derived data, where appropriate. 
Calculations performed by the computer may be checked by hand for 10 observations within the dataset, 
where appropriate. 
Analysis of the primary and secondary endpoints may be checked independently. 
 
 Definition of populations for Analysis 
Populations for analysis are defined as follows: 
Population for (DLT and tolerability) safety run-in analysis: patients receiving at least 5 out of 6 scheduled 
treatments, or withdrawing early due to drug-related toxicity, will contribute to the DLT and tolerability 
analysis. Patients who do not receive at least 5 out of the 6 scheduled treatments, except for reasons of drug-
related toxicity, will be excluded and replaced, such that there are 6 patients evaluable for tolerability. 
Safety population: all participants who receive at least part of one dose of trial treatment will be evaluable 
for the safety analyses. In the safety run-in part of the study, all safety population patients will be evaluable 


 
PemBla - Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) 
Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
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for AEs. In the main study, safety analysis of patient data will be undertaken according to the treatment 
actually received (not as randomised).  
Population for efficacy analysis: all analyses in the main trial will be on a modified intention-to-treat basis. 
This means that patients will be analysed as they are randomised irrespective of the treatment actually 
received. The intention-to-treat population will include all patients who have given their informed consent 
and for whom there is confirmation of successful allocation of a randomisation number. This will be modified 
by omitting patients without the endpoint/outcome measure.  
 
 Analyses to address primary aims 
The primary aim is to assess the safety, tolerability and toxicities of intravesical and intravenous 
pembrolizumab. 
9.1 
Intravesical safety run-in 
The number of patients experiencing a dose limiting toxicity (DLT) per cohort will be reported. Full details of 
all dose limiting toxicities will be listed. No formal comparison will occur between dose levels. 
A DLT is defined as a clinically significant, drug related, grade 4 haematological or > grade 3 non-
haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that 
patient. 
A summary of worst reported AEs will tabulated by cohort and graphs of worst adverse events over time will 
be produced and presented according to whether they are considered treatment-related or not. A summary 
of drug-related toxicities (as stated in the Protocol, table in Section 8.5) will also be given. 
A sensitivity analysis will be carried using the safety population treating patients who withdraw for toxicity 
without experiencing a DLT as having had a DLT. Patients who withdraw, prior to observing a DLT, for any 
other reasons will be excluded. 
9.2 
Main study (Phase II trial) 
The number and proportion of patients experiencing a grade 3-5 adverse event will be reported for each 
treatment group with 95% confidence intervals. The same analysis will be repeated for SAEs. Numbers and 
proportions with grade 1+ adverse events will also be reported. 
 
A summary of worst reported AEs will tabulated by treatment arm and graphs of adverse events over time 
will be produced. 
9.3 
Pre-specified Subgroup Analysis 
There are no pre planned subgroup analyses. 
9.4 
Treatment by Centre Interaction 
No analysis of within centre effects will be done. The trial will not recruit a sufficient number of patients to 
explore this. 
 Analysis to address secondary aims 
10.1 Efficacy 
 
Complete response of marker lesion (CR) occurs: 


 
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1. when the marker lesion is not visible (at surgery on day 85) and there is a negative tumour bed 
biopsy (pathological CR) or 
2. when the marker lesion is not visible (at surgery on day 85)  but there is no negative tumour biopsy 
i.e. microscopic evidence of tumour or no biopsy done/biopsy NE (clinical CR) 
 
The number and proportion of patients with a CR (and 90% CI) at TURBT on day 85 (± 7) will be reported for 
each treatment arm. A p-value comparing the data to the null hypothesis of p=0.2 will be computed (as per 
the A’Hern design). Patients who do not have TURBT will be treated as non-responders for the efficacy 
endpoint. 
There are no planned subgroup or sensitivity analyses. 
10.2 Recurrence and progression free interval 
Recurrence is defined as the appearance of at least one new lesion (in the bladder).  
Progression is defined as development of any of the following3:   
• 
T1 disease (lamina propria invasion) 
• 
> T2 disease (muscle invasive) 
• 
Lymph node (N1+) or distant metastases (M1) 
• 
High grade (G3) disease or CIS 
Since in this setting the definition of progression requires a worsening of disease staging patients may have a 
recurrence without progression. These events may also occur at the same time. 
Patient follow-up is for 2 years or until disease recurrence, progression or death whichever is sooner (Protocol 
V1.0 17Feb2017). Therefore, if there is progression (with or without recurrence, or vice versa), the patient will 
be withdrawn from the study.  
 
Recurrence free interval (RFI): Assessed from time of TURBT on day 85 (± 7) to recurrence or progression. 
Patients in whom there is no recurrence (within the bladder) will be censored at the last-known recurrence 
free follow-up or at time death. The patients included in the RFI analysis will be those remain on study at day 
85 (ie have not had recurrence, progression or died by day 85) , undergo TURBT and are not found to have 
had a recurrence at that time. 
Progression free interval (PFI): Assessed from time of randomisation to progression. Patients who do not 
progress will be censored at the time of recurrence or death or the last-known progression free follow-up. 
Kaplan‐Meier curves for RFI and for PFI will be presented for each treatment group, with RFI and PFI estimates 
given at 6 months, 1 year and 2 years along with 90% CI. 
There are no planned subgroup or sensitivity analyses. 
 
 Additional Analyses 
The analysis of the Tertiary / Exploratory endpoints will be detailed in a separate analysis plan being led by 
the WIMM (Weatherall Institute of Molecular Medicine, University of Oxford). All translational sample 
                                                          
 
3 Progression could theoretically occur without recurrence (dramatic progression of the marker lesion or 
nodal/metastatic disease without a new bladder tumour) but is very unlikely in this population. 


 
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Funded by the Oxford NIHR Biomedical Research Centre, CRUK Oxford Centre and an educational grant from the Merck Sharp & 
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Date: 03Nov2017 
 
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Page 18 of 18 
 
analysis will be performed between the WIMM and Qualtek (a 3rd party lab which has been contracted to do 
the PD-L1 analysis. CSM is not responsible for these analyses. 
 
 Appendix: Glossary of abbreviations  
AE 
 
Adverse events 
DLT 
 
Dose limiting toxicities 
SAE 
 
Serious adverse events 
CI 
 
Chief Investigator 
NMIBC  
Non-muscle invasive bladder cancer 
PFI 
 
Progression free interval 
RFI 
 
Recurrence free interval 
SAP 
 
Statistical Analysis Plan 
TM 
 
Trial Manager 
TMG 
 
Trial Management Group 
TURBT  
Transurethral Resection of Bladder Tumour 
 Changes from previous version of SAP 
A summary of key changes from earlier versions of SAP, with particular relevance to protocol changes that 
have an impact on the design, definition, sample size, data quality/collection and analysis of the outcomes 
will be provided. Include protocol version number and date. 
Version number 
Issue date 
Author of 
this issue 
Protocol Version & 
Issue date 
Significant changes from previous 
version together with reasons 
V1.0_02Nov2017 
Peter Dutton 
Joanna 
Moschandreas 
Protocol version 1.0 
17Feb2017 
Not applicable as this is the 1st issue 
V2.0_03Nov2017 
Peter Dutton 
Protocol version 2.0 
28Jul2017 
Updated to reflect ammendments to 
protocol 
 
 References 
 
A'Hern RP (2001) Sample size tables for exact single-stage phase II designs. Stat Med  20(6):859-66 
Brown S, Thorpe H, Hawkins K and Brown J (2005) Minimization – reducing predictability for multi-centre trials 
whilst maintaining balance within centre. Stat Med 24:3715-3727