Clinical trial NCT02662062
Conditions: Bladder Cancer
Keywords: Non-metastatic muscle invasive bladder cancer
Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Start date: 2017-07-11; Completion date: 2024-08-26
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will enrol patients with maximally resected (via transurethral resection (TURBT) non-metastatic muscle invasive bladder cancer, who either wish to attempt bladder preservation therapy or are ineligible for cystectomy. Patients must have adequate organ function and performance status to receive cisplatin based chemoradiotherapy, and no contraindications to the use of pembrolizumab. The study will enrol 30 patients to be treated with pembrolizumab and radiotherapy.

All patients will be planned to be treated with 64Gy of radiation therapy in 32 fractions over 6 weeks and 2 days. All patients will receive cisplatin 35mg/m2 IV concurrently weekly with radiation therapy for 6 doses total. Pembrolizumab will commence concurrently with radiation and be given 200mg IV every 21 days, continuing until the 12 week cystoscopy and assessment.

Surveillance cystoscopy will be performed 12 weeks after the commencement of chemoradiotherapy, and assess the rate of complete response to therapy. A safety follow up visit will occur 4 and 12 weeks post cystoscopy. From week 31 survival follow up will commence with clinical assessment, cystoscopy and CT staging performed at intervals until 5 years.

The objective of the study is to assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by complete response rate of the primary tumour at first post chemoradiotherapy cystoscopic assessment. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters.

It is expected that it will take two years to accrue the required 30 patients.

Detailed description:

Arms: arm 1: Pembrolizumab to be administered via IV 200mg 3 weekly commenced concurrently with chemoradiotherapy, and continuing until 12 week cystoscopy.
Interventions: intervention 1: Pembrolizumab intervention 2: Cisplatin intervention 3: Radiotherapy
Intervention descriptions: intervention 1: 200 mg/m2, IV (in the vein) on day 1 every three weeks (Weeks 1, 3, 7, 10, 13, 16 and 19). until progression or unacceptable toxicity develops. intervention 2: 35 mg/m2, IV (in the vein) every week for six weeks. intervention 3: 2.00Gy once daily for 32 fractions, 5 fractions/week over six weeks and two days (a total of 64Gy).

Protocol documents:
Prot_SAP_000.pdf: 
 
  
 
Pembrolizumab with ChemoRadiotherapy as treatment 
for Muscle Invasive Bladder Cancer:  
 
PCR-MIB Study 
 
 
Protocol Number  
ANZUP 1502 
 
VERSION NUMBER 
5.0 
DATE OF PROTOCOL 
  03 January 2018 
TRIAL ONCOLOGY PI 
Andrew Weickhardt 
Phone 
+61 3 9496 5763 
Fax 
+61 3 9457 6698 
Email 
andrew.weickhardt@onjcri.org.au  
TRIAL RADIATION PI 
Farshad Foroudi 
Phone 
+61 3 9496 2428 
Fax 
+61 3 9496 9647 
Email 
Farshad.foroudi@austin.org.au  
TRIAL UROLOGY PI 
Nathan Lawrentschuk 
Phone 
+61 3 9455 3363 
Fax 
+61 3 9457 5829 
Email 
urologyoncologist@gmail.com  
Participating Sites 
Olivia Newton-John Cancer Centre, Austin Hospital, Vic 
Peter MacCallum Cancer Institute, Vic 
Chris O’Brien Lifehouse, Royal Prince Alfred Hospital, NSW 
Prince of Wales Hospital, NSW 
Sir Charles Gairdner Hospital, WA 
Royal North Shore Hospital, NSW 
Clinical Trial Manager 
Laura Galletta – Centre for Biostatistics and Clinical Trials (BaCT) 
PCR-MIB ANZUP1502 Protocol version 5.0; dated: 03 January 2018 
Page 1 of 76 
 
 


 
SPONSOR 
Australian and New Zealand Urogenital & Prostate (ANZUP) Cancer Trials 
Group 
Address 
Level 6, 119-143 Missenden Road, Camperdown. NSW 2050 
Phone 
02 9562 5033 
Fax 
02 9562 5008 
Email 
Margaret@anzup.org.au  
 
CONFIDENTIAL 
This document contains confidential information. This information should not be disclosed, other 
than to those involved in the execution or ethical review of the study, without written 
authorization from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer 
Trials Group. 
COMPLIANCE STATEMENT  
This trial will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP). In addition, the trial will be conducted 
in compliance will all applicable laws and regulatory requirements relevant to the use of new 
therapeutic agents, Pembrolizumab in Australia and any other participating country. Agreement 
of the investigator(s) to conduct and administer this trial in accordance with the protocol and 
associated regulations will be documented in the trial agreements with the Sponsor and other 
forms required by national authorities in the country where the trial center is located. 
The Investigator(s) is responsible for ensuring the privacy, safety and welfare of the participants 
during and after the trial. 
The Principal Investigator at each center has the overall responsibility for the conduct and 
administration of the trial at their center, and for conduct with the trial center management, the 
Independent Ethics Committee (IEC) / Human Research Ethics Committee (HREC) and local 
authorities. 
The Protocol and all other trial related documentation including the Patient Informed Consent 
Form (PICF) and Case Report Form (CRF) must be written in English and under no 
circumstances be translated into another language without prior written approval from ANZUP.  
 
Variations to the Protocol 
No changes from the final approved (signed) protocol will be initiated without the ethics 
committee’s prior written approval of favorable opinion of a written amendment, except when 
necessary to eliminate immediate hazards to the participants or when the change involves only 
the logistics or administration.  
 
PCR-MIB ANZUP1502 Protocol version 5.0; dated: 03 January 2018 
Page 2 of 76 
 
 




 
TRIAL SPONSOR AND COORDINATING PRINCIPAL INVESTIGATOR 
SPONSOR: 
 
Australian & New Zealand Urogenital and Prostate 
Cancer Trials Group (ANZUP) 
 
SPONSOR REPRESENTATIVE: 
 
Ian Davis 
Street Address: 
 
c/- Level 6, 119-143 Missenden Road,  
PO Box: 
 
 
Suburb: 
 
Camperdown  
State: 
NSW 
 
Postcode 
 
2050 
Phone: 
 
+61 3 9094 9546 
Fax: 
 
+61 3 9899 9137 
Email: 
 
ian.davis@monash.edu  
 
 
COORDINATING PRINCIPAL 
INVESTIGATOR: 
A/Prof Andrew Weickhardt 
Hospital Street Address: 
 
145 Studley Road 
Suburb: 
 
Heidelberg 
State: 
Victoria 
 
Postcode 
 
3084 
Phone: 
 
+61 3 9496 5763 
After Hours Contact Number: 
 
+61 3 9496 5000 
Fax: 
 
+61 3 9457 6698 
Email: 
 
andrew.weickhardt@onjcri.org.au  
 
 
 
PCR-MIB ANZUP1502 Protocol version 5.0; dated: 03 January 2018 
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CONTENTS 
1.0 
TRIAL SUMMARY .................................................................................................. 11 
2.0 
TRIAL DESIGN ........................................................................................................ 12 
3.0 
OBJECTIVES, HYPOTHESES & ENDPOINTS .................................................. 14 
3.1 
Primary Objective, Hypothesis & Endpoints ..................................................... 14 
3.2 
Secondary Objectives, Hypothesis & Endpoint .................................................. 14 
3.3 
Exploratory Objective .......................................................................................... 15 
4.0 
BACKGROUND & RATIONALE .......................................................................... 15 
4.1 
Background ............................................................................................................ 15 
4.1.1 Background Chemoradiotherapy ......................................................................... 15 
4.1.2 Pharmaceutical and Therapeutic Background Chemoradiotherapy .................... 16 
4.1.3 Background Pembrolizumab ............................................................................... 17 
4.1.4 Pharmaceutical and Therapeutic Background Pembrolizumab ........................... 17 
4.1.5 Preclinical and Clinical Trial Data for Pembrolizumab ...................................... 18 
4.2 
Rationale for the combination of pembrolizumab with chemotherapy and 
radiation ................................................................................................................. 18 
4.2.1 Rationale for the Trial and Selected Participant Population ............................... 19 
4.2.2 Rationale for Dose Selection/Regimen Pembrolizumab ..................................... 19 
4.2.3 Rationale for Dose Selection/Regimen Cisplatin ................................................ 20 
4.2.4 Rationale for Endpoints ....................................................................................... 20 
5.0 
METHODOLOGY .................................................................................................... 22 
5.1 
Entry Criteria ........................................................................................................ 22 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 22 
5.1.2 Participant Inclusion Criteria............................................................................... 22 
5.1.3 Participant Exclusion Criteria ............................................................................. 23 
5.1.4 Registering a Patient – General Guidelines ......................................................... 25 
5.2 
Study Assessments ................................................................................................. 26 
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5.2.1 Evaluation during screening period ..................................................................... 26 
5.2.2 Evaluation during chemoradiotherapy period ..................................................... 26 
5.2.3 Evaluation during pembrolizumab treatment period ........................................... 27 
5.2.4 Evaluation at end of treatment visit (Week 23 or when patient ceases treatment)27 
5.2.5 Evaluations at post treatment review visit (Week 31 or 12 weeks post last 
treatment)............................................................................................................. 28 
5.2.6 Evaluations during follow-up .............................................................................. 28 
5.3 
Chemoradiotherapy Trial Treatments ................................................................ 29 
5.3.1 Trial Treatment Information ................................................................................ 29 
5.3.2 Dose Modifications ............................................................................................. 31 
5.3.3 Timing of Dose Administration .......................................................................... 35 
5.3.4 Radiation Schedule .............................................................................................. 35 
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 40 
5.4.1 Acceptable Concomitant Medications ................................................................. 40 
5.4.2 Prohibited Concomitant Medications .................................................................. 40 
5.5 
Rescue Medications & Supportive Care for Pembrolizumab ........................... 41 
5.5.1 Supportive Care Guidelines................................................................................. 41 
5.6 
Diet/Activity/Other Considerations ..................................................................... 44 
5.6.1 Diet ...................................................................................................................... 44 
5.6.2 Contraception ...................................................................................................... 44 
5.6.3 Use in Pregnancy ................................................................................................. 45 
5.6.4 Use in Lactating Women ..................................................................................... 45 
5.7 
Participant Withdrawal/Discontinuation Criteria ............................................. 46 
6.0 
TRIAL FLOW CHART............................................................................................ 47 
6.1 
Study Flow Chart .................................................................................................. 47 
7.0 
TRIAL PROCEDURES ............................................................................................ 49 
7.1 
Trial Procedures .................................................................................................... 49 
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7.1.1 Administrative Procedures .................................................................................. 49 
7.1.2 Clinical Procedures/Assessments ........................................................................ 50 
7.1.3 Laboratory Procedures/Assessments ................................................................... 54 
7.1.4 Other Procedures ................................................................................................. 54 
7.1.5 Visit Requirements .............................................................................................. 54 
7.1.6 Treatment Period ................................................................................................. 55 
7.2 
Assessing and Recording Adverse Events ........................................................... 55 
7.2.1 Adverse Event (AE) ............................................................................................ 56 
7.2.2 Unexpected Adverse Events (UAE) .................................................................... 56 
7.2.3 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Sponsor ..................................................................... 57 
7.2.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 57 
7.2.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck .............. 58 
7.2.6 Evaluating Adverse Events ................................................................................. 60 
7.2.7 Adverse Event Reporting .................................................................................... 60 
7.2.8 SAE Reporting .................................................................................................... 61 
7.2.9 Sponsor Responsibility for Reporting Adverse Events and Serious Adverse 
Events .................................................................................................................. 63 
8.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 63 
8.1 
Statistical Analysis Plan Summary ...................................................................... 63 
8.2 
Sample Size Calculation ....................................................................................... 65 
8.3 
Methods of analysis ............................................................................................... 67 
8.4 
Exploratory analysis ............................................................................................. 68 
8.5 
Timing of Analyses ................................................................................................ 69 
9.0 
SAFETY parameters/review AND MODIFICATIONS TO TRIAL ................... 69 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 70 
10.1 
Investigational Product ......................................................................................... 70 
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10.2 
Packaging and Labeling Information .................................................................. 70 
10.3 
Clinical Supplies Disclosure ................................................................................. 70 
10.4 
Storage and Handling Requirements .................................................................. 70 
10.5 
Returns and Reconciliation .................................................................................. 71 
11.0 
STUDY COMMITTEES .......................................................................................... 71 
11.1 
Trial Management Committee ............................................................................. 71 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 71 
12.1 
Confidentiality ....................................................................................................... 71 
12.2 
Protocol Amendments ........................................................................................... 71 
12.3 
Data Handling and Record Keeping ................................................................... 72 
12.4 
Compliance with Trial Registration and Results Posting Requirements ........ 72 
12.5 
Quality Management System ............................................................................... 73 
12.6 
Audit and Inspection ............................................................................................. 73 
12.7 
Statistical Report ................................................................................................... 73 
12.8 
Publication Policy .................................................................................................. 73 
13.0 
APPENDICES ........................................................................................................... 74 
13.1 
ECOG Performance Status .................................................................................. 74 
13.2 
Common Terminology Criteria for Adverse Events V4.03 (CTCAE) ............. 74 
14.0 
REFERENCES .......................................................................................................... 75 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time  
BaCT 
Centre for Biostatistics and Clinical Trials 
CIS 
Carcinoma in situ 
CrCl 
Creatinine Clearance 
CT C/A/P 
CT Chest/abdomen/pelvis 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
DICOM 
Digital Imaging and Communications in Medicine 
DNA 
Deoxyribonucleic acid  
DMFS 
Distant Metastasis Free Survival 
DVH 
Dose Volume Histograms 
ECOG 
Eastern Cooperative Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture system 
ERC 
Ethics Review Committee 
FBE 
Full Blood Examination 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus  
HREC 
Human Research Ethics Committee 
ICRU 
International Commission on Radiation Units 
IMRT 
Intensity Modulated Radiation Therapy 
INR 
International Normalized Ratio 
LFT 
Liver function tests 
LRPFS 
Locoregional Progression Free Survival 
OS 
Overall Survival 
pCR 
Pathological Complete Response; equivalent to pT0 
PD1 
Programmed cell death 1 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin time 
PTV 
Planning Target Volume 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TCC 
Transitional cell carcinoma (urothelial bladder cancer) 
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TIL 
Tumor-infiltrating lymphocytes 
TMC 
Trial management committee 
TOE 
Trials operations executive 
TSH 
Thyroid-Stimulating Hormone 
TURBT 
Transurethral resection of bladder tumour 
UECr 
Urea, Creatinine and Electrolytes 
ULN 
Upper limit of normal 
UT 
Unacceptable Toxicity 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
PCR-MIB 
Pembrolizumab with ChemoRadiotherapy for Muscle 
Invasive Bladder cancer 
Trial Phase 
Phase II 
Clinical Indication 
Patients with nonmetastatic, muscle invasive bladder cancer 
who either wish to attempt bladder preservation therapy or 
are ineligible for cystectomy. 
Trial Type 
Pilot single arm study: Non-randomized cohort of 
pembrolizumab with chemoradiotherapy 
Type of control 
No control arm/placebo 
Route of administration 
Radiation: 64Gy of radiation therapy in 32 fractions over 6 
weeks and 2 days. 
Chemotherapy (concurrent with radiation): IV concurrent 
weekly cisplatin 35mg/m2 (6 weeks) 
Pembrolizumab: 
IV 
200mg 
3 
weekly 
commenced 
concurrently with chemoradiotherapy, and continuing until 
12-week cystoscopy 
Trial Blinding 
Nil 
Treatment Groups  
30 
patients, 
treated 
with 
pembrolizumab 
and 
chemoradiotherapy 
Number of trial 
participants 
30 patients 
Estimated enrolment 
period 
2 years; 5 sites 
Estimated duration of trial 2 years of accrual + 3 years follow up 
Duration of Participation 
19 weeks of study visits; then end of treatment and follow up 
visits 
Objectives 
Primary: 
To 
demonstrate 
that 
the 
addition 
of 
pembrolizumab to chemoradiotherapy for muscle invasive 
bladder cancer is feasible as measured by a satisfactorily 
low rate of unacceptable toxicity.  
Secondary:   
1. 
To evaluate the efficacy of the addition of 
pembrolizumab to concurrent chemoradiation regimen 
using the best response achieved, as assessed by cystoscopy 
at weeks 19 and 31 of the trial (12 and 24 weeks post 
completion of chemoradiotherapy). 
2. 
To characterize:  
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a. overall survival (OS); 
b. metastatic disease-free survival (DMFS); and  
c. locoregional progression free survival (LRPFS). 
Exploratory: To evaluate tumour histopathological, 
molecular genetics, and immunological parameters and 
their relationship with response to chemoradiotherapy and 
pembrolizumab. 
 
 
 
 
2.0 TRIAL DESIGN 
This pilot study will enroll patients with maximally resected (via transurethral resection 
(TURBT) non-metastatic muscle invasive bladder cancer, who either wish to attempt bladder 
preservation therapy or are ineligible for cystectomy. Patients must have adequate organ function 
and performance status to receive cisplatin based chemoradiotherapy, and no contraindications to 
the use of pembrolizumab. The study will enroll 30 patients to be treated with pembrolizumab 
and chemoradiotherapy.  
All patients will be planned to be treated with 64Gy of radiation therapy in 32 fractions over 6 
weeks and 2 days. All patients will receive cisplatin 35mg/m2 IV concurrently weekly with 
radiation therapy for 6 doses total. Pembrolizumab will commence concurrently with radiation 
and be given 200mg IV every 21 days, continuing until the 12week cystoscopy and assessment. 
Surveillance cystoscopy will be performed 12 weeks after the commencement of 
chemoradiotherapy, and assess the rate of complete response to therapy.   End of treatment and 
post treatment review visits will occur 4 (i.e. week 19) and 12 (i.e. week 31) weeks post 
cystoscopy. After the week 31 post treatment visit, patients will enter follow up with clinical 
assessment, cystoscopy and CT staging performed at intervals until close of study. 
The objective of the study is to assess the safety and feasibility of combining pembrolizumab 
with chemoradiotherapy. The primary endpoint assessed will be safety, as defined by a 
satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of 
planned chemotherapy and radiotherapy according to defined parameters). The secondary 
endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of 
complete response, considering the   first two post chemoradiotherapy cystoscopic assessments, 
at 19 and 31 weeks. Exploratory analysis will include assessment of tumour histopathological, 
molecular, genetic and immunological parameters. 
It is expected that it will take two years to accrue the required 30 patients. 
 
 
 
 
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Figure 1: Study Flow Chart and Key Assessments
 
 
*Patients in follow up receive clinical assessment 3 monthly for 12 months, 6 monthly for 18 months, and 12 monthly thereafter for a minimum 
of 3 years or until death. Cystoscopy and CT C/A/P is performed within 28 days of each of these clinical assessments.  
 
^ Week 7 pembrolizumab dose will occur in same week as last 2 days of radiotherapy. 
 
Prestudy 
Assessments 
Chemoradiotherapy 
Pembrolizumab 
Adjuvant Period 
End of 
Treatment 
Post  
Treatment 
Review 
Follow 
Up 
Week 
To be 
completed 28 
days after 
ceasing 
treatment at any 
time and for 
any reason. 
To be 
completed 12 
weeks post 
ceasing 
treatment for 
any reason 
 
Within 6 weeks 
1 
2 
3 
4 
5 
6 
7 
10 
13 
16 
19 
23 
31 
 
Clinical 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cisplatin 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Radiotherapy 
 
X 
X 
X 
X 
X 
X 
X^ 
 
 
 
 
 
 
 
Pembrolizumab 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
TURBT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cystoscopy 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Urine Cytology 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
CT C/A/P 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
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3.0 OBJECTIVES, HYPOTHESES & ENDPOINTS 
3.1 
Primary Objective, Hypothesis & Endpoints 
Objective: To demonstrate that the addition of pembrolizumab to chemoradiotherapy for 
muscle invasive bladder cancer is feasible as measured by a satisfactorily low rate of 
unacceptable toxicity. 
Hypothesis:  Pembrolizumab in combination with chemoradiotherapy will be safe and well 
tolerated in patients with previously untreated muscle invasive bladder cancer. 
Endpoints: Occurrence of an unacceptable toxicity affecting patients where an unacceptable 
toxicity is defined by any of the following:  
a) Occurrence of a grade 3 or 4 acute toxicity (excluding grade 3 or 4 urinary toxicity), 
occurring either during treatment or within 12 weeks after scheduled completion of treatment, 
or 
b) Cisplatin being withheld for > 2 doses  
c) Cisplatin doses being withheld or reduced such that <66% of the intended total cisplatin 
dose is delivered 
d) Radiation treatment being delayed beyond more than 7 weeks 
e) Any single pembrolizumab dose being delayed for more than 6 weeks. (Multiple dose 
delays will not be aggregated). 
3.2 
Secondary Objectives, Hypothesis & Endpoint 
 
Objectives:   
(1) To evaluate the efficacy of the addition of pembrolizumab to concurrent chemoradiation 
regimen by estimating the complete response rate (see below). 
(2) To characterize:  
a. overall survival (OS); 
b. metastatic disease-free survival (MDFS); and  
c. locoregional progression free survival (LRPFS). 
 
Hypothesis:  The addition of pembrolizumab will improve the efficacy of chemoradiation in 
patients with bladder cancer. 
Endpoints:  
(1) Best response, defined as the better of the responses achieved at either the 1st or 2nd 
cystoscopic examination after completing therapy. (The 1st and 2nd cystoscopic 
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examinations take place during weeks 19 and 31 respectively of the trial.) See section 
7.1.2.6.2 for definitions of the response levels. 
(2) Dates of 
i) 
death,  
ii) 
detection of metastatic disease,  
iii) 
detection of locoregional progression, 
iv) 
any initiation of any new non-protocol anti-cancer therapy 
 
3.3 
Exploratory Objective 
Objective: To describe tumour histopathological, molecular genetics, and immunological 
parameters and their relationship with response to chemoradiotherapy and pembrolizumab. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Background Chemoradiotherapy 
Treatment options for muscle invasive bladder cancer are cystectomy, or chemoradiotherapy, 
with salvage cystectomy [1]. Chemoradiotherapy is a suitable treatment for patients with muscle 
invasive bladder cancer who are ineligible for cystectomy, or who wish to preserve their bladder 
[2]. Cystectomy has a 2-3% procedural mortality rate, higher in smokers, the elderly and patients 
with medical comorbidities [1]. There are detrimental changes on the quality of life of patients 
related to the use of an ileal conduit, sexual dysfunction and body image. Five year survival rates 
are between 30-75%, depending on the stage of the tumour (T2 – 66%, T3 35%, T4 27%) [3] [4]  
Five year overall survival rates of 40-60% from both prospective and retrospective series are 
comparable between patients who undergo cystectomy, and patients who undergo 
chemoradiotherapy with salvage cystectomy for treatment failure [5] . The only randomized trial 
comparing chemoradiotherapy to cystectomy was too small to provide estimates of survival 
effects [6].  
Additionally a significant proportion of patients will keep their bladder [2]. Chemotherapy, such 
as cisplatin, acts a radiosensitising agent when used with radiotherapy [7]. The rationale of 
chemoradiation is that chemotherapy increases the effectiveness of radiation, acting as a 
cytoreductive agent and radiation sensitizer. Chemotherapy may also improve outcomes by 
treating micrometastatic disease. In the BC 2001 trial comparing chemoradiotherapy with 
5FU/MMC to radiation alone, 2 year locoregional relapse was reduced to 18% vs 32% in the 
radiotherapy arm [8].  
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4.1.2 Pharmaceutical and Therapeutic Background Chemoradiotherapy 
Multiple different chemotherapy regimens have been used in combination with radiation for 
bladder cancer. Reported efficacy and safety are similar between different regimens as 
summarized in the table[2].  
 
Contemporary chemoradiotherapy series report similar outcomes related to relevant tumour 
related endpoints including complete response rates, 5-year disease free survival, 5 year overall 
survival, and rates of distant metastatic disease regardless of chemotherapy regimen. There 
appears no significant benefit from additional chemotherapy administered before or after the 
concurrent chemoradiotherapy and this does not form part of usual practice in Australia[2].  
 Salvage treatment with cystectomy plays an important role in managing patients with 
chemoradiotherapy and is the gold standard for optimal trimodality therapy should patients 
relapse. Two approaches here have been reported for patients considered fit for salvage 
cystectomy. Firstly in the MGH and RTOG protocols, response evaluation is performed after 
approximately 40Gy of induction therapy [5, 9]. Only complete responders are considered 
eligible for bladder preservation therapy and proceed with consolidation treatment with the 
bladder treated up to 64Gy. Conversely, a second alternative is the Erlangen approach [10], 
where the bladder is evaluated at 4-6 weeks post definitive chemoradiotherapy. The late-response 
evaluation may theoretically increase the chance of bladder preservation, as some slow 
responders may still be responding and have not maximally regressed after the 40Gy of 
treatment. Additionally, split dose radiotherapy is of some concern. However, the two 
approaches seem equally effective in terms of long term survival and bladder preservation. This 
study will utilize the latter approach. 
An early assessment of efficacy of chemoradiation that is standardly used is the complete 
response rate, which is determined in most series to be based on first cystoscopic assessment of 
the bladder cancer 12 weeks after chemoradiotherapy is completed [1, 5]. This involves 
examination under anesthesia, cystoscopy and biopsy of all previously positive tumor sites that is 
utilized to evaluate the tumor status (response) following completion chemoradiotherapy. In 
some patients radiographic or cystoscopic evaluation will reveal abnormalities at the bladder 
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tumor-site (such as thickening of the wall, ulcerations, or possible nodularities) which contain no 
identifiable tumor cells histologically. Patients will be considered as having a complete response, 
or pT0 response, when the bi-manual examination under anesthesia is negative, when all the 
biopsies are negative for any tumor at the site(s) of the pretreatment tumor(s) and there is an 
absence of metastatic disease on the most recently performed systemic imaging. 
4.1.3 Background Pembrolizumab 
Pembrolizumab is a novel antibody to PD1, which has shown activity as an immunomodulating 
agent in a range of cancers. In preliminary trials of pembrolizumab in metastatic bladder cancer, 
26% of patients experienced a radiological response, and at least 60% of patients had tumour 
shrinkage [11].  
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on pembrolizumab. 
4.1.4 Pharmaceutical and Therapeutic Background Pembrolizumab 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors 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 signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
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endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in participants with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  
Phase 3 trials of pembrolizumab in metastatic bladder cancer are currently underway. 
4.1.5 Preclinical and Clinical Trial Data for Pembrolizumab 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale for the combination of pembrolizumab with chemotherapy and radiation 
Chemoradiotherapy leads to outcomes similar to cystectomy. However, a significant proportion 
of patients still fail to achieve a complete response to chemoradiation, require a cystectomy, 
relapse locally, or develop distant metastatic disease.  
Approximately 30% of patients fail to achieve a complete response to therapy, with a relapse rate 
of 10% with local-regional disease, and 9-20% distant metastatic disease over 2 years [1, 2, 7, 
12]. Improvements in these outcomes are desired. 
The use of drugs such as pembrolizumab is transforming cancer medicine, and checkpoint 
inhibitors are resulting in unprecedented disease response rates and longer-term control. 
However, while a subgroup of bladder cancer demonstrate exquisite responses to these agents, 
many patients do not derive any benefit.  A major challenge therefore is to develop rational 
strategies by which the activity of these agents can be broadened.   
One potential approach is the combination of immunotherapy with radiation therapy.  Radiation 
therapy induced cell killing has the potential to stimulate the release of tumour antigens and 
trigger antigenic stimulation.  Proof of this concept is provided by in vitro studies [13], and 
anecdotally from clinical observations of tumour regressions at unirradiated tumour sites (the 
abscopal effect). Importantly, the combination of radiotherapy with immune check point 
inhibitors has been reported to escalate antitumour responses in clinical case reports [14], and 
shown to be safe when combined with radiation in several trials [15]. The effect of this 
combination in bladder cancer however has not been extensively investigated.   
Predicting the impact of combining chemotherapy with immunotherapy is less straightforward. 
While chemotherapy may deplete immune effector cells, the cytotoxic effects of chemotherapy 
may also enhance antigen-release and stimulate immune responses as postulated for radiation 
therapy. In preclinical mouse models, chemotherapy synergises with anti-PDL1 treatment to 
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induce durable anti-tumour responses and treatment with chemotherapy increases the number of 
tumour-infiltrating CD8+ cells [16] In mice chemotherapeutic agents such as 5FU induce greater 
cytotoxicity towards myeloid-derived suppressor T-cells, and therefore may serve to enhance 
immune function [17]. Addressing the safety and efficacy of combining immunotherapy with 
chemotherapy is therefore an important question. To-date, anti-PD1 drugs have been safely 
combined with chemotherapy in lung cancer with little additional toxicity and with robust 
responses that support the potential synergy of the combination [16, 18]. Specifically 
pembrolizumab has been safely combined with chemotherapy [18] with only 1 dose limiting 
toxicity out of 24 treated patients, however the efficacy results have not yet been published. 
Large phase 3 trials of pembrolizumab in combination with cisplatin chemotherapy are currently 
recruiting in gastric (KEYNOTE 062) and head/neck squamous cancers (KEYNOTE 048) 
amongst others.  
4.2.1 Rationale for the Trial and Selected Participant Population 
4.2.2 Rationale for Dose Selection/Regimen Pembrolizumab 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in participants 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose 
tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol 
to test for initial tumor activity.  Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of pembrolizumab were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200mg fixed dose regimen relative to a 2 
mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
4.2.3 Rationale for Dose Selection/Regimen Cisplatin 
Cisplatin dosing has not been uniform across the multiple clinical trials in bladder cancer when 
used as a radiosensitiser. A commonly accepted regimen is cisplatin given weekly at 35mg/m2 
for a total of 6 doses, and this was used in the TROG 99.06 trial [12]. In this study 3/36 patients 
(8%) required 2 or more doses of cisplatin to be omitted, and 3/36 (8%) had 1 dose omitted.  
4.2.4 Rationale for Endpoints 
4.2.4.1 Safety and Efficacy Endpoints 
Rates of serious adverse events (Grade 3-4) in chemoradiotherapy trials are generally low, and 
reported between 5-30% [7, 8, 19]. The radiotherapy discontinuation rate has been reported to be 
between 0-5% [7, 8, 12, 19]. The radiotherapy completion rate in TROG 99.06 was 95%[12]. 
The grade 3-4 urinary G3 toxicity was 23% and G3 GI toxicity occurred in 2% [12].  
The standard early assessment of efficacy from bladder cancer chemoradiotherapy trials is the 
complete response rate, as assessed by the 6-12 week cystoscopic assessment of the bladder after 
commencing chemoradiotherapy. Contemporary series for complete response rates are 
approximately 70-85% [20] [1, 2, 6, 8, 19].  
Outcomes regarding complete pathological response rate depends on the extent of the initial 
TURBT, which is reported in the literature at experienced centers to be 65-87% [5, 9].  Patients 
with a visually complete TURBT have a pCR rate of 73-79%, compared to patients with an 
incomplete pCR rate of 50-63%. The 5 year survival rate is also different between these groups 
57 vs 43% [5, 9].   
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Other endpoints of note and contemporary outcomes include 2 year disease free survival of 60-
70% [5, 7], 5 year overall survival of 45-72% [5, 9].  The distant metastatic disease rate has been 
reported between 17-29% [21, 22]. 
The primary and secondary endpoints for the study will be  
Primary 
The primary objective is to assess feasibility of pembrolizumab in combination with 
chemoradiation, as measured by a satisfactorily low rate of unacceptable toxicities in the patient 
sample.  
The primary endpoint is thus unacceptable toxicity, and is defined as either: 
a) occurrence of a grade 3 or 4 toxicity (excluding grade 3 or 4 urinary toxicity), occurring 
either during treatment or within 12 weeks after scheduled completion of treatment, or 
b) failure to complete chemoradiation as planned: prescribed dose of radiation delivered 
within a maximum 7 weeks; administration of full dose cisplatin without dose reduction or 
omission of more than two doses; and administration of full dose pembrolizumab without 
delay of more than 6 weeks. 
Secondary 
The first secondary objective is to test for an initial efficacy signal, as measured by the complete 
response (CR) rate.  
The first secondary endpoint, CR, is defined as achievement of pT0 at either the 1st or 2nd 
cystoscopic examination. 
The additional secondary objectives are to document (over the 3-5 years of follow up for 
patients) 
- 
overall survival  
- 
metastatic disease-free survival; and  
- 
locoregional progression free survival 
The corresponding secondary endpoints are thus the dates of death, detection of metastatic 
disease, and detection of locoregional progression, where applicable. Date of initiation of non-
protocol anti-cancer therapy will also be collected as part of the definition of DMFS and LRPFS. 
4.2.4.2 Biomarker Research 
Preliminary reports of the activity of PD1 inhibitors in bladder cancer correlate outcomes in 
relation to response to therapy in the metastatic setting with expression of PDL1 on tumour 
infiltrating immune cells [11]. Further work is required for biomarker discovery and validation 
when PD1 inhibitors are used with chemoradiotherapy. 
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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Histologically-confirmed diagnosis of muscle-invasive T2-T4a, Nx or N0 urothelial cell 
carcinoma of the bladder. Subjects with tumors of mixed transitional/non-transitional cell 
histology are allowed, but transitional cell carcinoma must be the predominant histology (>50%). 
Subjects with predominant or exclusively non-transitional cell histology are not allowed. 
5.1.2 Participant Inclusion Criteria 
In order to be eligible for participation in this trial, the participant must: 
1. Be willing and able to provide written informed consent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
Have histologically-confirmed diagnosis of muscle-invasive T2-T4a, Nx or N0 urothelial 
cell carcinoma of the bladder. Subjects with tumors of mixed transitional/non-transitional 
cell histology are allowed, but transitional cell carcinoma must be the predominant 
histology (>50%). Subjects with predominant or exclusively non-transitional cell 
histology are not allowed.  
 
3. Must have undergone maximal transurethral resection of the bladder tumour, as is judged 
as safe as possible by the urologist performing the resection, within 42 days of planned 
treatment commencement. Where patient has only had a biopsy/partial resection and is 
otherwise eligible for entry into the study, the case should be rediscussed with the 
referring urologist to see whether further resection would be feasible prior to embarking 
with the chemo-radiotherapy. 
 
4. Have elected not to undergo radical cystectomy, or are unsuitable for radical cystectomy. 
 
5. Planned for chemoradiotherapy as definitive treatment. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale 
7. Demonstrate adequate organ function as defined in Table 2. All screening labs should be 
performed within 10 days of registering the patient on the trial. 
Table 2: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1.5 X 109/L 
Platelets 
≥100 X 109/L 
Hemoglobin 
≥90 g/L without transfusion or EPO dependency (within 7 
days of assessment) 
Renal 
 
Calculateda creatinine clearance 
 
≥40 mL/min  
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
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Direct bilirubin ≤ ULN for participants with total bilirubin 
levels > 1.5 ULN 
AST and ALT  
≤ 2.5 X ULN 
Albumin 
>25 g/L 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy 
(as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants) 
 
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy (as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants) 
aCreatinine clearance at screening should be calculated using Cockroft-Gault methodology, or 
measured with either a 24 hour urinary CrCl, or a nuclear medicine DTPA/ETDA scan 
 
8. Female participants of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to registering the patient.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.   
9. Female participants of childbearing potential should be willing to use two methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the course 
of the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Participants of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
10. Male participants should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
11. Willing to consent to the use of their collected tumour specimen, blood and urine as 
detailed in the protocol for future scientific research including but not limited to DNA, 
RNA and protein based biomarker detection. 
5.1.3 Participant Exclusion Criteria 
The participant must be excluded from participating in the trial if the participant: 
1. Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) urothelial cell carcinoma 
of the urothelium. Patients who have involvement of the prostatic urethra with urothelial 
cell cancer (TCC) that was visibly completely resected and no evidence of stromal 
invasion of the prostate remain eligible. 
 
2. Evidence of tumour-related moderate/severe hydronephrosis unless stented or with 
nephrostomy to preserve renal function. 
 
3. Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative 
chemoradiotherapy. 
 
4. Bulky T3/T4a tumours unsuitable for curative treatment (i.e. >10 cms in any dimension); 
node positive disease. 
 
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5. Evidence of distant metastatic disease on CT chest/abdomen/pelvis performed within 42 
days prior to study entry. Patients with pelvic lymph nodes deemed to be ‘positive’ are 
not eligible for the study unless histological confirmation of the largest most suspicious 
node is negative for malignancy. Patients with known CNS metastatic disease are 
excluded from the study 
 
6. Prior pelvic radiotherapy 
 
7. Has had prior intravenous chemotherapy, targeted small molecule therapy, or radiation 
therapy for treatment of bladder cancer. Prior intravesical use of BCG and mitomycin is 
permissible. 
 
8. Unsuitable for concurrent cisplatin based chemoradiotherapy based on: 
- 
CTCAE v.4.03, Grade >2 audiometric hearing loss (25dB in two consecutive 
wave ranges) if previously performed. 
- 
CTCAE v.4.03, Grade >2 peripheral neuropathy 
 
9. 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 
4 weeks prior to the first dose of treatment. 
 
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to registering the patient. 
Patients with adrenal insufficiency receiving replacement dose steroids are allowed on the 
trial. 
 
11. Has a known history of active TB (Bacillus Tuberculosis) 
 
12. Hypersensitivity to pembrolizumab or any of its excipients. 
 
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 
14. Prior or concurrent known additional malignancy of any site unless disease free for 5 
years. 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, Stage 
T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5) 
 
15. Has any history of active autoimmune disease, Stevens-Johnson syndrome or Guillain-
Barre. Exceptions to this are: 
- 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone 
- 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen who 
are also be eligible for this study  
 
16. Has known history of, or any evidence of active, non-infectious pneumonitis. 
 
17. Has an active infection requiring systemic therapy. 
 
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18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the participant to participate, in the 
opinion of the treating investigator.   
 
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
 
21. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
22. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
23. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
24. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
5.1.4 Registering a Patient – General Guidelines 
Sites will register eligible patients electronically using the online PCR-MIB electronic data 
capture (EDC) system. Confirmation of registration will also be provided electronically (via 
email) as well as, a unique 5-digit patient identification number for the patient.   
Full training on the PCR-MIB EDC system will be provided to sites prior to site activation. 
Prior to patient registration, the investigator should ensure that all of the following requirements 
are met: 
• 
The patient meets all inclusion criteria and none of the exclusion criteria should 
apply. 
• 
The patient has signed and dated all applicable consent forms.  
• 
All baseline assessments and investigations have been performed. 
• 
The eligibility checklist has been completed, signed and dated. 
• 
Ensure any support test/investigation reports to be provided to the Trial Centre are de-
identified 
 
N.B. You will NOT be able to register a patient if treatment has commenced or if consent has not 
been given. 
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Following registration patients should begin protocol treatment within 10 days. Issues that would 
cause treatment delays should be discussed with the Coordinating Principal Investigator (CPI).  
A patient who withdraws consent prior to commencement of pembrolizumab and 
chemoradiotherapy may be replaced to ensure 30 patients in total are treated with the 
combination. 
For any queries contact the Centre for Biostatistics and Clinical Trials (BaCT) at Peter Mac. 
5.2 
Study Assessments 
5.2.1 Evaluation during screening period 
Screening evaluation (within 6 weeks of treatment start date) shall include:  
1. Comprehensive medical history 
2. Documentation of concomitant medications at time of screening 
3. Full physical examination  
4. Documentation of ECOG performance status 
5. Vital signs  
6. Radiological evaluation with a CT Chest/Abdomen and Pelvis must be performed within 
6 weeks of treatment starting 
7. Laboratory studies no more than 10 days prior to the treatment start include FBE, UECr, 
LFTs, TSH and coagulation 
8. Pregnancy test in female patients with child bearing potential  
9. Cystoscopic evaluation by the participating urologist including a thorough as possible 
transurethral resection of the bladder tumour, bimanual examination under anesthesia, as 
well as a biopsy of the base of the resected tumour site. Patients referred from outside 
with incomplete resections will be considered for re-resection if considered feasible by 
the urologist prior to chemoradiation. Complete description of the location of tumour, 
size, morphology, extravesical spread, CIS, ureteric involvement will be provided by the 
urologist performing the cystoscopy. 
5.2.2 Evaluation during chemoradiotherapy period 
During the chemoradiotherapy period the following assessments are to be performed within 3 
days prior to the start of each week of radiotherapy unless otherwise specified below. 
1. Adverse events 
2. Vital signs 
3. Concomitant medications 
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4. ECOG performance status 
5. Directed physical examination 
6. Laboratory tests (FBE, UECr, LFTs) within 3 days of the administration of chemotherapy 
or pembrolizumab. A TSH,T3, T4 is taken every 6 weeks 
7. Documentation of new anticancer therapies 
8. Collection of blood and urine samples for biomarker studies (Week 1) 
If these assessments have taken place during the screening evaluation (5.2.1) within 10 days of 
treatment commencement, these do not need to be repeated for the first week of therapy. 
Note that biomarker blood and urine samples are to be taken on day 1 of therapy with 
pembrolizumab prior to therapy, please refer to the PCR-MIB Biomarker Laboratory Manual for 
further blood sampling information. 
5.2.3 Evaluation during pembrolizumab treatment period 
The following assessment will take place within 3 days of each scheduled pembrolizumab 
treatment between week 7 and 19:  
1. Adverse events 
2. Vital signs 
3. Concomitant medications 
4. ECOG performance status 
5. Directed physical examination 
6. Laboratory tests (FBE, UECr, LFTs). A TSH, T3, T4 is taken every 6 weeks 
7. Radiological evaluation (CT Chest/Abdo/Pelvis) at week 19  
8. Cystoscopy assessment at week 19  
9. Urine cytology at week 19 
10. Collection of blood and urine samples for biomarker studies at Week 7 
Note that biomarker blood and urine samples are to be taken on Week 7 of therapy with 
pembrolizumab prior to therapy, please refer to the PCR-MIB Biomarker Laboratory Manual for 
further blood sampling information. 
5.2.4 Evaluation at end of treatment visit (Week 23 or when patient ceases treatment) 
The following assessment will take place at the end of treatment visit, when a patient ceases 
treatment for progression, unacceptable toxicities or any other reason: 
1. Adverse events 
2. Vital signs 
3. Concomitant medications 
4. ECOG performance status 
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5. Directed physical examination 
6. Laboratory tests (FBE, UECr, LFTs). A TSH, T3, T4 is taken every 6 weeks 
7. Radiological evaluations (CT Chest/Abdo/Pelvis)*   
8. Cystoscopy assessments* 
9. Urine cytology* 
10. Documentation of new anticancer therapies 
11. Documentation of disease status 
12. Collection of blood and urine samples for biomarker studies 
* CT chest/abdomen/pelvis, cystoscopy and urine cytology only need to be performed at End of 
Treatment visit if these assessments have not been performed at Week 19, for instance if the 
patients has come of study for toxicity prior to Week 19.   
5.2.5 Evaluations at post treatment review visit (Week 31 or 12 weeks post last treatment) 
1. Adverse Events 
2. Vital signs 
3. ECOG performance status 
4. Directed physical examination 
5. Laboratory tests (FBE, UECr, LFTs). A TSH, T3, T4 is taken every 6 weeks 
6. Radiological evaluation 
7. Cystoscopy assessment 
8. Urine cytology 
9. Documentation of new anticancer therapies 
10. Documentation of disease status 
11. Survival status 
5.2.6 Evaluations during follow-up 
After the end of treatment study visit, patients enter into follow up for OS, LRPFS and DMFS. 
Follow up for these survival endpoints will be 3 monthly for 12 months after the post treatment 
review visit, then 6 monthly for 18 months, then 12 monthly until 3 years after the registration of 
the last patient or study closure. The following assessments will take place at each visit: 
 
1. Vital Signs 
2. Directed physical exam 
3. Urine cytology 
4. Post-study anticancer therapy status 
5. Disease Status 
6. Survival status 
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7. Radiological evaluation (CT Chest/Abdo/Pelvis)  
8. Cystoscopy assessment 
Patients with either local or distant progression do not require vital sign, directed physical 
examination, urine cytology, or cystoscopy assessment at each visit.  
Patients with local progression should continue to receive radiological evaluation for assessment 
of distant metastatic disease. Patients with distant progression should receive radiological 
evaluation at the discretion of the investigator. 
5.3 
Chemoradiotherapy Trial Treatments 
The treatment to be used in this trial is outlined below: 
Table 3:  Trial Treatment 
Treatment 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Cisplatin 
35mg/m2 
(30mg/ m2 if 
CrCl 40-50) 
Weekly, 
synchronous 
during 
radiotherapy 
IV infusion 
Weekly during radiotherapy 
for total 6 doses 
Radiotherapy 
64Gy in 32 
fractions  
5 daily 
fractions per 
week over 6.4 
weeks. 
3D- 
Conformal 
External 
Beam 
Radiotherapy 
64Gy 
Pembrolizumab 
200 mg IV 
Q3W 
IV infusion 
Day 1 of each 3 week cycle, 
until week 12 cystoscopy, 
for total 7 doses 
 
5.3.1 Trial Treatment Information 
5.3.1.1 Cisplatin 
5.3.1.2 Description of Cisplatin  
Cisplatin is an antineoplastic compound which is a planar inorganic metal salt supplied as a 
lyophilised powder. It functions as an alkylating agent by producing interstrand and intrastrand 
crosslinks which modifies DNA structure and prevents DNA synthesis. It also inhibits RNA and 
protein synthesis.  
 
5.3.1.3 Supply of Cisplatin  
Sandoz, Hospira and Pfizer all produce cisplatin. Investigators can nominate to use any brand of 
Cisplatin that is readily available at their sites. Cisplatin will be provided to study participants 
according to usual hospital practice, and in Australia will be funded through the Pharmaceutical 
Benefits Scheme (PBS). Medication labels will be provided by the participating institution’s 
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Pharmacy Department and will comply with requirements of the Australian Therapeutic Goods 
Administration. Cisplatin will be dispensed as per standard pharmacy practice. 
5.3.1.3.1 Administration of cisplatin 
Cisplatin chemotherapy will commence on the same day as radiation therapy. After 1000ml 
sodium chloride 0.9% is administered as prehydration (10mmol MgS04 is allowed to be added as 
per institutional preference), cisplatin 35mg/m2 in 1000mL sodium chloride 0.9% will be 
administered over 60 minutes. Cisplatin is commercially available. Conceivably the co-
administration of dexamethasone with the chemotherapy may reduce lymphocyte counts and 
efficacy of pembrolizumab. Therefore, the dose of dexamethasone administered with 
chemotherapy will be 4mg IV rather than 8mg unless > G2 nausea/vomiting develops. The 5HT3 
antagonist palonosetron 0.25mg IV (or equivalent 5HT3 antagonist) will be given prior to 
cisplatin. Other antiemetic use such as aprepitant and/or olanzapine is permissible. 
Dexamethasone 4 mg IV premedication given prior to cisplatin is permitted and allowed to 
continue at dose < 4mg orally daily for 2 days after administration. Increase in dexamethasone 
dose is permitted in discussion with the principal investigator. Urine output measurement is not 
necessary before cisplatin administration as high urine flow does not appear to be protective.  
Cisplatin will be administered weekly during radiotherapy at 7 day intervals 
The chemotherapy is to be given preferably at the beginning of each week of treatment and as far 
as possible on the same day of the week (or within no more than 72 hours) on each occasion 
throughout the course of treatment.  
No more than 6 doses of cisplatin will be administered. 
Patients’ renal function and myeloid function will be assessed within 72 hours prior to 
administration of each dose of cisplatin.  
The patient should be assessed by the doctor prior to proceeding with each dose of 
chemotherapy. 
Dose modification is described in 5.3.2.1. 
5.3.1.4 Pembrolizumab 
5.3.1.4.1 Description of pembrolizumab 
Pembrolizumab is a novel antibody to PD1, administered intravenously. 
5.3.1.4.2 Supply of pembrolizumab 
Pembrolizumab will be supplied in the form of 100mg vials. Details of supply, handling and drug 
accountability are included in the Pharmacy Manual.  
5.3.1.4.3 Administration of pembrolizumab 
Pembrolizumab 200mg IV, q3 weekly will be given on the same day as the cisplatin, 
commencing on day 1 (or within no more than 72hrs) of radiotherapy, and given every 3 weeks 
(weeks 1, 4, 7, 10, 13, 16 and 19).  
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Pembrolizumab 200 mg will be administered as a 30 minute IV infusion. Sites should make 
every effort to target infusion duration to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion duration is 30 minutes: -5 min/+10 min). 
Pembrolizumab will continue after chemoradiotherapy has been completed (weeks 7, 10, 13, 16 
and 19) for a total of 7 doses for the whole study, culminating with the 7th dose at week 19 of the 
study (12 weeks post completion of chemoradiotherapy). Pembrolizumab will continue for up to 
7 doses total so long as there is 
- no evidence of distant metastatic spread before this time 
- no intervening administration of new anti-cancer therapy  
-  no evidence of locoregional progression 
- no radiotherapy administered aside from that dictated in the protocol 
- no pembrolizumab related AE severe toxicities as detailed in Table 6, Section 5.3.2.2 
that require pembrolizumab to be withheld or discontinued. 
5.3.1.4.4 Pembrolizumab Adjuvant Treatment 
After chemoradiotherapy, patients will receive pembrolizumab in weeks 7, 10, 13, 16 and 19 
(radiation will be scheduled for 2 days in week 7, but cisplatin will not be administered).  
Pembrolizumab 200mg IV treatment may be administered up to 3 days before or after scheduled 
the day of each cycle due to administrative reasons but should occur on the same day. Treatment 
will finish at week 19. 
In the event of a treatment delay due to an adverse event outlined in Table 6, patients may 
resume pembrolizumab within 3 weeks of the due dose. Subsequent dosing of pembrolizumab 
will continue until week 19, but not beyond this regardless of the total number of doses that the 
patient has received. 
Cystoscopic assessment of tumour response will take place in week 19 and week 31, and is 
described in Section 7.1.2.6. 
5.3.2 Dose Modifications 
5.3.2.1 Cisplatin 
Modifications of cisplatin for nephrotoxicity during radiotherapy are listed below. CrCl should 
be calculated using the Cockroft-Gault methodology. During radiation therapy, CrCl is to be 
recalculated each week, within 3 days of cisplatin administration. 
 
 
 
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Table 4:  Dose modification of cisplatin dosing based on recalculation of the CrCl 
 
 
 
 
 
 
 
Dose increases for patients commenced at 30mg/m2 are permitted should renal function improve 
(based on weekly recalculation of CrCl) during radiotherapy and after discussion with the study 
chair. 
An FBE is to be performed within 3 days of each cisplatin administration. Modification 
parameters for cisplatin dose reduction are displayed below. 
 
Table 5: Dose modification cisplatin based on neutrophil/platelet count 
ANC 
Platelet Count x109 
Value 
>150 
75-149 
<75 
> 1.4 
100% 
100% 
75% 
0.8 – 1.4 
100% 
75% 
75% 
< 0.8 
0% 
0% 
0% 
 
5.3.2.2 Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 6 below. See Section 5.5.1 for 
supportive care guidelines, including use of corticosteroids. 
 
 
Renal Function 
Cisplatin 
Dosing 
CrCl >50:  
35mg/m2 
CrCl >40 but <50: 
30mg/m2 
CrCl >30 but <40 
25mg/m2 
CrCl <30  
Withhold 
dose 
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Table 6:  Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse Events 
 
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 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE 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 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
Grade 4 
Permanently 
discontinue 
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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 β-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  
Hyperthyroidis
m  
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.  
 
Nephritis 
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 
• 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate 
evaluation to 
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AEs 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
confirm etiology 
and/or exclude 
other causes 
 
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).   
 
Dosing of cisplatin and radiation can proceed despite the development of pembrolizumab related 
adverse events with the exception of the dose modifications described specifically in the sections 
related to cisplatin and radiation.  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Participants should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Coordinating Principal Investigator. 
The reason for interruption should be documented in the patient's study record. 
5.3.3 Timing of Dose Administration 
Pembrolizumab should be administered on Day 1 of commencement of chemoradiotherapy after 
all procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).   
Pembrolizumab 200mg IV will be given in weeks 1, 4, 7, 10, 13, 16 and 19. Treatment may be 
administered up to 3 days before or after the scheduled day of each cycle due to administrative 
reasons. 
In the event of a treatment delay due to an adverse event outlined in Table 6, patients may 
resume pembrolizumab within 12 weeks of the due dose so long as the toxicity has resolved to 
Grade 1 or less and the patient is on a dose of 10mg or less of prednisolone or equivalent. 
Subsequent dosing of pembrolizumab will continue until week 19, but not beyond this regardless 
of the total number of doses that the patient has received. 
All trial treatments should be administered on an outpatient basis unless discussed with the 
Principal Investigator/Sponsor. 
5.3.4 Radiation Schedule 
The information provides detail on the generation of the conventional image guided radiotherapy. 
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5.3.4.1 
Statement of treatment aim and rationale 
The aim of this study is to deliver a radical dose of radiotherapy to the entire bladder volume for 
eligible participants who provide informed consent. A dose of 64Gy in 32 fractions over 6 weeks 
and 2 treatment days is prescribed. 
The radiotherapy plan is used to deliver treatment for fractions 1 to 32 using a standard planning 
approach with daily image guidance using Cone Beam CT (CBCT).  
5.3.4.2 Credentialing 
Sites will complete one credentialing case for completion, submission and approval prior to 
commencement of radiotherapy. Details of the credentialing process are in the Radiation Manual.  
5.3.4.3 Treatment Schedule 
Radiotherapy will commence according to standard departmental protocols but not more than 42 
days after TURBT. If delays of longer than this are anticipated then a second TURBT is 
permitted to achieve maximum resection of the tumour prior to radiation.  
5.3.4.4 Planning Simulation  
CT based planning using standard departmental imaging guidelines is required. Scan properties 
(thickness, width) should enable accurate delineation of all structures and facilitate the 
construction of high quality transverse, sagittal and coronal plane reconstructions as well as 
digital reconstructed radiographs (DRRs). Scan thickness and width of equal to or less than 3mm 
is recommended. 
Scan volume should include the entire bladder volume and all relevant organs at risk. It is 
recommended that scan extents are L4 – ischial tuberosities. 
Patient positioning is to be supine using standard departmental guidelines, using appropriate 
immobilization. Simulation and treatment position must be identical. 
An empty bladder is required for all imaging and treatment processes, all participants must void 
immediately prior to simulation. Where a participant is unable to void or has a residual bladder 
volume, any further simulation options to ensure a minimum bladder volume are at the 
prescribing Radiation Oncologist’s discretion.  
Rectal preparation is not required, however, the rectal cross section at the central CT slice should 
be <4.0cm in diameter. Where a rectal diameter is >4.0cm, instruct the patient to return to the 
bathroom and attempt to pass gas or faecal material. Rescan and review the rectal diameter. In 
cases where the diameter continues to exceed 4.0cm, any further simulation options to reduce the 
rectal cross-sectional diameter are at the prescribing Radiation Oncologist’s discretion.  
Surface markers should be placed at a minimum on skin surface to define the CT reference point 
and marked with a permanent/semi-permanent marker for subsequent identification at the 
treatment phase. Additional markers along the midline (minimum of two) are required to assist 
with alignment and markers on the lateral pelvis to assist with correction of rotation are also 
required. Measurements of all reference and marker points should be recorded.  
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5.3.4.5 Target volume definitions/Field Borders 
5.3.4.5.1 Target Volumes 
Target Volumes are defined from the planning CT, these include: 
• 
Clinical Target Volume (CTV) - The clinical target volume (CTV) should include the 
whole bladder, the tumour bed region, the proximal urethra and, in the male patient, if there 
is involvement of the bladder neck and/or prostatic fossa, the entire prostatic urethra. 
Patients who have had a previous prostatectomy and bladder neck involvement should have 
urethra covered for a distance of 2 cm distal to the bladder neck. Any extra-vesical 
extension (e.g. peri-vesical fat) will be included in the CTV. No attempt will be made to 
cover nodal groups including first echelon lymph nodes (obturator) in the immediate 
vicinity of the bladder. Unusual anatomical variations (e.g. cystoceles and diverticula) 
should be covered. In cases involving the ureteric orifice, the distal ureter should be 
covered to a distance of 1 cm. 
 
• 
Planning Target Volume - Will be created by a CTV to PTV expansion of  
• Laterally 0.8cm 
• Anteriorly 1.5cm 
• Posteriorly 1.2cm 
• Superiorly 1.5cm 
• Inferiorly 0.8cm 
 
5.3.4.6 Normal tissue contouring 
The rectum and right and left femurs must be contoured on the planning simulation CT scan.  
Organ at risk delineation and dose constraints include: 
Rectum:  
• 
Delineation: Rectal volume to be marked as a solid structure from the upper field border to 
the lower field border.  
 
Femurs:  
• 
Delineation: Femurs are contoured from acetabulum to a lower extent equal to the most 
inferior border of the field edge. 
 
5.3.4.7 Dose prescription and Fractionation: 
5.3.4.7.1 Total Dose and Dose per Fraction 
The total dose prescribed is 64Gy.  
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Dose fractions of 2.00Gy are required to be delivered once daily for 32 fractions, 5 
fractions/week. In the event of a treatment interruption for any reason, the missing dose 
fraction(s) should be made up according to the instructions provided in 5.3.4.7.2. 
The reason for any treatment interruption must be documented.  
5.3.4.7.2 Treatment Duration 
The total treatment duration is 6 weeks and 2 treatment days. Treatment should be completed 
from commencement unless severe acute toxicity is observed.  
Where an interruption occurs: 
 
A minor radiation protocol deviation is recorded when the treatment extends from 6.4 up to 
7 weeks 
 
A major radiation protocol deviation is recorded when the treatment extends beyond 7 
weeks 
 
Strategies for managing treatment interruptions (planned or unplanned) include 
 
Treating 6 fractions per week preceding or following a week where 4 fractions are 
delivered 
 
Treating twice a day with a 6hr treatment interval where treatment is not possible on a 
scheduled day 
 
Substituting a weekend day for a week day where treatment is not possible on a pre-
programmed day 
 
Note: No more than 6 fractions may be given in any one week. 
 
Note: The reason for any treatment interruption must be documented.  
 
5.3.4.8 Treatment Planning and Dosimetry 
5.3.4.8.1 Planning System Requirements 
The requirements for planning systems are described in the separate Radiation Manual.  
5.3.4.8.2 Beam Arrangements 
There is no prescribed beam arrangement; individual departments are free to use established 
treatment protocols provided 3 or more fields are employed. 
Inverse Planned IMRT, volumetric modulated arc therapy and techniques are allowed if sites are 
credentialed. 
 
5.3.4.8.3 Lipiodol Injection for Target Volume Delineation and Image 
Guidance 
The use of bladder tumour demarcation with lipiodol injection through flexible cystoscopy is 
permitted if used as standard of care at the treating center to optimize radiation planning and 
image guidance. Lipiodol may be injected in the bladder wall prior to radiation planning 
consistent with previous publications highlighting the benefits of injecting small 0.25ml deposits 
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circumferential pattern around the primary tumour or resection site, with excess lipiodol removed 
with irrigation [23]. This must be done prior to radiation planning and commencement.  
5.3.4.8.4 Treatment Techniques not permitted 
• 
Techniques utilising beam energies less than 6MV are not permitted. 
• 
Techniques delivered using the following equipment is not permitted 
 
Gamma Knife 
 
Helical Tomotherapy 
 
CyberKnife 
 
Protons 
 
5.3.4.8.5 Compensation and heterogeneity corrections  
The requirements for compensation and heterogeneity corrections are in the Radiation Manual 
5.3.4.8.6 Dose distribution/Reporting 
The requirements for dose distribution/reporting are in the Radiation Manual 
 
5.3.4.9 Treatment Verification and Delivery 
For all fractions, treatment verification is based on soft tissue based placement derived from a 
pre-treatment cone beam CT. All isocentre offsets identified on CBCT should be corrected daily 
(i.e. 0cm action threshold – any offset greater than or equal to 1mm should be corrected).  
If the bladder size is larger than the PTV size the patient will be requested to void their bladder 
and another verification CBCT should be performed prior to treatment delivery. 
5.3.4.9.1 Treatment Verification 
Treatment Verification comprises the following: 
• 
Daily treatment unit based cone beam CT prior to treatment to ensure soft tissue based 
Isocentre placement (all fractions)  
• 
Repeat treatment unit based cone beam CT prior to treatment where an initial target CT 
demonstrates a residual bladder volume that does not fit into a conventional 1.5cm plan. 
 
Treatment verification using daily treatment unit based cone beam verification CT should be 
completed from commencement of treatment without interruption. 
Where a treatment unit based cone beam CT cannot be completed, alternative management 
strategies will require: 
 Use of standard departmental imaging protocols (2D planar KV or MV EPI bone based) 
on-line and with a zero threshold value. 
 
The reasons for interruption to daily treatment unit based verification cone beam CT must be 
recorded. 
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5.3.4.9.2 Data Submission: 
Details of data submission requirements are found in the PCR-MIB Radiation Manual. 
 
5.3.4.9.3 Treatment Equipment Specifications/Physical factors 
All participants must be treated using external beam radiotherapy on a linear accelerator.  
The following specifications apply to equipment used: 
• 
Energy: 6MV or greater  
• 
MLC size: 1.0cm or smaller 
• 
Cone Beam Factors include: 
 
Minimum 15cm scan length 
 
Volumetric with minimum slice spacing of 3mm 
 
kVp greater or equal to 120kVp 
 
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Coordinating principal investigator.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participant’s primary physician.  
5.4.1 Acceptable Concomitant Medications 
During the period of chemoradiotherapy, dexamethasone 4 mg IV premedication given prior to 
cisplatin is permitted and allowed to continue at dose < 4mg orally daily for 2 days after 
administration is permissible. After completion of chemoradiotherapy corticosteroids equivalent 
up to 10mg per day of prednisone is permissible upon discussion with study chair.  
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs as 
defined in Section7.2. 
5.4.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
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• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids is allowed. The use of dexamethasone with cisplatin chemotherapy is 
permitted as described in 5.3.1.3.1 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Participants may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5 
Rescue Medications & Supportive Care for Pembrolizumab 
5.5.1 Supportive Care Guidelines 
Participants 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 etiology are outlined below. 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 is permitted if necessary.   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 as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines below are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.  
Refer to Section 5.3.2.2  for timing for restarting treatment and discontinuation criteria. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids 1-2mg/kg prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 -6 weeks.  
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o For Grade 3-4 events, or recurrent Grade 2, immediately treat with systemic 
intravenous corticosteroids 1-2mg/kg prednisone or equivalent. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 -6 weeks. Administer additional anti-inflammatory measures, as 
needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
o Cisplatin and radiation can continue despite pneumonitis if judged safe by 
investigators 
 
• Diarrhea/Colitis:  
Participants should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All participants who experience 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, treat with systemic 
corticosteroids 1-2mg/kg prednisone or equivalent., then tapering over 4-6 weeks.  
If Grade 2 diarrhea persists despite steroids for more than 3 days, management 
should be escalated to treat patient with IV steroids, and pembrolizumab withheld 
until colitis resolves to Grade 0-1  
o For Grade 3 or 4 diarrhea/colitis, treat with systemic intravenous corticosteroids 
1-2mg/kg prednisone or equivalent.   
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 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, 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.  
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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 non-selective beta-blockers (eg, propranolol) or thionamides as 
appropriate. 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).and treat with 0.5-1mg systemic prednisone or 
equivalent. 
o For Grade 3-4 events, treat with intravenous 1-2mg/kg corticosteroids for 24 to 
48 hours then 0.5-1mg systemic prednisone or equivalent. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. Permanently 
discontinue pembrolizumab. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
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.  
Table 7 shows treatment guidelines for participants who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
 
 
 
 
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Table 7: 
 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
<=24 hrs. 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Participant is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
5.6 
Diet/Activity/Other Considerations 
5.6.1 Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.6.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
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breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Participants should start using 
birth control from study Visit 1 throughout the study period and continue until 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study, they must adhere to the contraception requirement (described above) for the duration of 
the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck.  If there is any question that a participant will not reliably 
comply with the requirements for contraception, that participant should not be entered into the 
study. 
5.6.3 Use in Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will immediately be removed from the study.  It is the responsibility of the site 
investigators or their designees to report all pregnancy exposures within 24 hours of becoming 
aware to the BaCT Trial Centre and to Merck Global Safety using the trial specific Pregnancy 
Reporting Form.  The site will continue to contact the participant at least monthly and document 
the participant’s status until the pregnancy has been completed or terminated.  The outcome of 
the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to 
the Sponsor and to Merck if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male participant 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in 
Section 7.2.4. 
5.6.4 Use in Lactating Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the lactating 
infant, participants who are breast-feeding are not eligible for enrolment. 
 
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5.7 
Participant Withdrawal/Discontinuation Criteria 
Participants may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. A patient who withdraws consent 
prior to commencement of pembrolizumab and chemoradiotherapy may be replaced to ensure 30 
patients in total are treated with the combination. In addition, a participant may be withdrawn by 
the investigator or the Sponsor if enrolment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4– Other Procedures. 
A participant must be discontinued from trial treatment for any of the following reasons: 
• Confirmed radiographic locoregional or metastatic disease progression 
• Initiation of new anti-cancer therapies 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the participant 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The participant is lost to follow-up 
• Administrative reasons 
• The participant or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Patient decision to withdraw 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 5.2.6 (Evaluations during follow-up)    
After the end of treatment visit, each participant will be followed as per the follow-up schedule 
outlined in Section 5.2.6. Participants will be followed until end of study or until withdrawal of 
consent, for disease status, initiation of new anticancer therapies, and overall survival.  
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6.0 TRIAL FLOW CHART 
6.1 
 Study Flow Chart 
 
 
Screen
ing 
Chemoradiotherapy 
Pembrolizumab Treatment Period 
End of Treatment (j) 
Post Treatment 
Review 
 
Follow Up (l) 
-42 to 
-1 
days 
Week 
Week 
To be completed 28 
days after ceasing 
treatment at any time 
and for any reason. 
To be completed 12 
weeks post ceasing 
treatment for any 
reason 
1 
2 
3 
4 
5 
6 
7 
10 
13 
16 
19 
23 
31 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Assessment (a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab Tests (b) 
FBE 
UECr 
LFTs 
TSH, T3, T4 
Coagulation 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Cisplatin 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Radiotherapy 
 
X 
X 
X 
X 
X 
X 
X (i) 
 
 
 
 
 
 
 
Pembrolizumab (c) 
 
X 
 
 
X 
 
 
X (i) 
X 
X 
X 
X 
 
 
 
Imaging 
CT Ch/Abdo/Pelvis (d) 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X (k) 
X 
X 
Cystoscopy(e) 
X 
 
 
 
 
 
 
 
 
 
 
X 
X (k) 
X 
X 
Urine Cytology 
 
X 
 
 
 
 
 
 
 
 
 
X 
X (k) 
X 
X 
Biomarker blood (f) 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Urine for biomarker 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pregnancy Test (g) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events (h) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Post-study anticancer 
therapy Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Documentation of 
Disease Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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a. Clinical Assessment: Pre-Treatment - Prior medical and therapeutic history (including concomitant medications, histological documentation of malignancy, full physical exam, ECOG 
performance status, vital signs and prior anticancer therapy.  During Treatment and End of Treatment Visits- adverse events, vital signs, concomitant medications, ECOG performance 
status and directed physical examination. ECOG performance status assessment during screening must take place within 10 days of treatment. During Follow-Up:  Vital signs, ECOG 
performance status and directed physical exam. 
b. Laboratory tests need to be performed within 3 days of each treatment related visit, except for the first visit, when these can be performed within 10 days.  
c. Pembrolizumab given if no contraindications based on AE assessment 
d. CT chest/abdomen/pelvis. Note:  Both oral and IV contrast is required. In the event of known allergy to contrast, an MRI abdomen/pelvis may be performed as an alternative. Method of 
tumour assessment should be consistent throughout all visits Additional scans as clinically indicated.  
e. Any additional cystoscopic assessmentis at the clinician discretion during this period.  
f. Blood – 50ml of blood drawn at each of 3 visits: as per the PCR-MIB Biomarker Laboratory Manual  
g. Patients should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. 
h. Adverse Events: To be graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.03 
i. Week 7 Pembrolizumab dose will occur in same week as last 2 days of radiotherapy 
j. End of treatment review occur either at Week 23, or 28 days after last treatment for patients who discontinue for either progression before week 19, or other reason i.e. toxicity  
k. CT chest/abdomen/pelvis, cystoscopy and urine cytology only need to be performed at End of Treatment visit if these have not been performed at Week 19, for instance if patients has 
come of study for toxicity prior to Week 19.   
l.Follow Up visits will be 3 monthly for 12 months after the End of Treatment visit, then 6 monthly for 18 months, then 12 monthly thereafter under study closure, with cystoscopic 
assessment, urine cytology collection and CT C/A/P within 28 days of each follow up visit. Patients with either local or distant progression do not require vital sign, directed physical 
examination, urine cytology, or cystoscopy assessment at each visit. Patients with local progression should continue to receive radiological evaluation for assessment of distant metastatic 
disease. Patients with distant progression should receive radiological evaluation at the discretion of the investigator 
. 
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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.   
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the HREC/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to HREC/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the bladder 
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cancer for which the participant has enrolled in this study will be recorded separately and not 
listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior therapy for bladder cancer 
The investigator or qualified designee will review and record prior treatment for urothelial 
cell bladder cancer. 
 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 
30 days after the last dose of trial treatment, the End of Treatment visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the participant 
will move into follow-up.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.03 (see Section 13.2).  AEs will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
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7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.   
7.1.2.3 Directed Physical Exam 
For visits that do not require a full physical exam per the Trial Flow Chart (Section 6.0), the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, at treatment discontinuation and at follow-up 
as specified in the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, 
pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening 
only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG performance status at screening, 
prior to the administration of each dose of trial treatment and at treatment discontinuation as 
specified in the Trial Flow Chart (Section 6.0).   
7.1.2.6 Tumor Imaging and Assessment of Disease 
7.1.2.6.1 Radiological Assessment 
Baseline CT Chest/Abdomen/Pelvis will be performed within 42 days of beginning 
treatment, then at week 19 and 31 prior to the end of treatment visit (+/- 7 days). The scan 
will be performed with IV contrast unless this is contraindicated due to renal insufficiency.  
Imaging before this time point is at the investigators discretion, with the exception of when 
patients have documented local progression at the time of their first cystoscopy. In this case, 
patients require a CT scan of chest/abdomen/pelvis within 2 weeks of the cystoscopy. 
Patients will have subsequent CT C/A/P restaging at week 19 (+/- 7 days), week 31 (+/- 7 
days) and then within 28 days of each scheduled follow up visit.  
7.1.2.6.2 Cystoscopic Assessment 
Assessment of disease with cystoscopy will take place within 42 days of commencement. 
The initial re-evaluation will take place 12 weeks (week 19 of trial) after completing 
chemoradiotherapy (+/- 7 days) (week 19 of the trial). Evaluation will include urine cytology, 
rigid cystoscopy, tumour site biopsy if indicated and bimanual examination after TUR.  
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The second check cystoscopy is mandatory at 24 weeks after completing chemoradiotherapy 
(+/- 7 days) (week 31 of the trial). Evaluation will include urine cytology, rigid cystoscopy, 
tumour site biopsy if indicated and bimanual examination after TUR. 
In follow up, patients will receive cytoscopic assessment every 3 months for 12 months after 
week 31, then 6 monthly for 18 months, then 12 monthly until 3 years after the last patient is 
registered. 
Any additional cystoscopic assessment (ie 6 weeks post chemoradiotherapy) is at the 
clinician discretion. 
At the cystoscopic assessments for response (weeks 19 and 31), patients will be determined 
to have either achieved a Complete Response, Partial Response, Stable Disease or 
Progressive Disease. The determination will be based upon the results of the urologist 
assessment of the bladder at cystoscopy, histological parameters and result of most recent 
systemic imaging, as follows.  
Patients will be considered as having a complete response, or pT0 response, when: i) the bi-
manual examination under anesthesia is negative,  ii) all the biopsies are negative for any 
tumor at the site(s) of the pretreatment tumor(s), and iii) there is an absence of metastatic 
disease on the most recently performed systemic imaging. 
Patients will be considered to have a partial response, when patients have a lower T stage 
(depth of invasion of tumour) on tumour biopsy than pretreatment tumour T stage and there 
is an absence of metastatic disease on the most recently performed systemic imaging.  
Patients will be considered to have stable disease when patients have the same T stage 
(depth of invasion of tumour) on tumour biopsy compared to pretreatment tumour T stage 
and there is an absence of metastatic disease on the most recently performed systemic 
imaging. 
Patients will be considered to have progressive disease where there is a higher T stage 
(depth of invasion of tumour) on tumour biopsy compared to pretreatment tumour T stage or 
distant metastatic disease, or locoregional nodal involvement on the most recently performed 
systemic imaging or there is the requirement for intravesical therapy. 
 
 
 
 
 
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Table 8:  
Determination of response to chemoradiotherapy 
 
Cystoscopic 
appearance 
Histological 
Grade 
Distant 
Metastatic 
Disease on 
Systemic 
Imaging* 
Nodal 
Involvement(1) 
 
Initiation of 
any new 
anticancer 
therapies  
(including 
Intravesical 
Therapy) 
Complete 
Response 
(all conditions 
satisfied) 
Bi-manual 
examination 
under anesthesia 
is negative  
(required at first 
and second 
cystoscopy) 
All biopsies 
negative for 
active tumour 
Absent 
Absent 
 
Partial 
Response 
(all conditions 
satisfied) 
 
Lower T stage 
Absent 
Absent 
 
Stable Disease 
(any condition 
satisfied) 
 
Same T stage 
 
Absent 
Absent 
 
Progressive 
Disease 
(any condition 
satisfied) 
 
Higher T stage 
 
Present 
Present 
Administered 
(1) Single or multiple regional lymph node metastasis in the true pelvis (hypogastric, obtrurator, external iliac or 
presacral lymph node). All other nodes above the aortic bifurcation are considered distant lymph nodes. 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Patients participating in the study will sign for consent for the use of their tissue for 
correlative biomarker studies. The Biomarker Laboratory Manual gives detailed instructions 
on specimens required and handling. Biomarker evaluable material includes 
Tumour 
Tissue: 
 
1) Formalin fixed paraffin blocks (or slides where block is not available) from 
resected tumour prior to treatment commencement 
2) Formalin fixed paraffin blocks (or slides where block is not available) from 
any recurrent or residual tumour 
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Blood: 
Peripheral blood taken prior to treatment commencement, at week 7 and week 
23. 
Urine: 
Mid-stream urine taken prior to treatment commencement, at week 7 and week 
23. 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial can 
be found in the PCR-MIB Biomarker Laboratory Manual. 
 
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.   
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
Within 42 days prior to treatment commencement, potential subjects will be evaluated to 
determine that they fulfil the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor. Results of a test performed 
prior to the subject signing consent as part of routine clinical management are acceptable in 
lieu of a screening test if performed within the specified time frame. Screening procedures 
are to be completed within 28 days prior to the first dose trial treatment except for the 
following: 
 
• Laboratory tests and evaluation of ECOG performance status are to be performed within 10 
days prior to the first dose of trial treatment 
 
• For women of reproductive potential, a urine pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment. If urine pregnancy results cannot be confirmed 
as negative, a serum pregnancy test will be required (performed by the local study site 
laboratory). 
 
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7.1.6 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart for both the  
1) Chemoradiation 
2) Pembrolizumab treatment period 
 
Specific procedure-related details are provided for this period in Section 6. 
 
 
7.1.6.1 End of Treatment and Post Treatment Review Visits 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart for both the  
1) End of Treatment visit (week 23) 
2) Post Treatment Review visit (week 31) 
 
The end of treatment visit must be completed within 30 days of ceasing treatment. The post 
treatment review must be completed 12 weeks post ceasing treatment. 
 
Specific procedure-related details are provided for this period in Section 6. 
 
 
7.1.6.2 Follow-Up Visits 
The follow-up period will extend for 3 years from the registration of the last patient enrolled.  
Visits will include clinical assessment, physical assessment, imaging, cystoscopy, urine 
cytology, documentation of disease status and new anti-cancer therapies and documentation 
of survival status. 
 
Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, detection of metastatic disease determined by the investigator/site 
and radiologist, death or end of study.  
 
Subjects who have completed the post treatment review visit will move into follow-up and 
will be assessed until 3 years after registration of the last patient. After the post treatment 
review visit, follow-up visits will occur as follows: 
• 3 monthly for 12 months 
• 6 monthly for 18 months 
• 12 monthly thereafter for a minimum of 3 years or until study close-out. 
 
7.2 
Assessing and Recording Adverse Events 
All adverse events will be recorded from the time the consent form is signed through to the 
commencement of follow up visits. The reporting timeframe for adverse events meeting any 
serious criteria is described in section 7.2.6.1. The investigator at each trial site is responsible 
for assessing and reporting AEs as part of patient safety, routine clinical care and data 
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collection. A subset of AEs will be classified as ‘serious’ and will require expedited 
reporting.  
All AEs that occur prior to the commencement of the follow-up visits should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within a 12-week period (90 days) post completion of adjuvant pembrolizumab should 
also be followed and recorded.   
7.2.1 Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product (or any other protocol 
specified intervention including Radiation Therapy, surgery or use of a device) and does not 
necessarily have to have a causal relationship with this treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product or protocol-specified procedure, whether or not considered 
related to the medicinal product or protocol-specified procedure.   
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. Laboratory values need reporting as AEs 
only if abnormal and deemed clinically significant by the investigator. 
AEs include: ‘Adverse Drug Reactions’, i.e. a reaction, in contrast to an event, is 
characterised by the fact that a causal relationship between the drug and the occurrence is 
suspected. 
For unapproved medicines: all noxious and unintended responses to a medicinal product 
related to any dose should be considered adverse drug reactions. The phrase ‘responses to a 
medicinal product’ means that a causal relationship between a medicinal product and an 
adverse event is at least reasonably possible, i.e. the relationship cannot be ruled out. 
Regarding marketed medical products: a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
diseases or for modification of physiological function.   
7.2.2 Unexpected Adverse Events (UAE) 
An Unexpected Adverse Event is an AE for which the nature or severity of the event is not 
consistent with the information in the relevant source documents e.g. the IB, published 
information, product information (or with the applicable side effect risk profile for radiation 
therapy, surgery or use of a device).  
UAEs include: ‘Unexpected Adverse Drug Reactions’, i.e. 
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The nature and severity of the ADR is not consistent with the information in the Investigators 
Brochure for an unapproved investigational product, or the product information/package 
insert/summary of product characteristics for an approved product. 
7.2.3 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Sponsor 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the participant should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of Pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
If a dose of Pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported as an SAE within 
24 hours to the BaCT Trial Centre and to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220). 
7.2.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a participant 
(spontaneously reported to them), including the pregnancy of a male participant's female 
partner that occurs during the trial or within 120 days of completing the trial, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever 
is earlier.  All participants and female partners of male participants who become pregnant 
must be followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
It is the responsibility of the site investigators or their designees to report such events within 
24 hours to the BaCT Trial Centre and to Merck Global Safety using the trial specific 
Pregnancy Reporting Form. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
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7.2.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.5.1 Serious Adverse Events 
 Adverse events and adverse drug reactions are considered ‘serious’ if they threaten life or 
function.  
SAEs include: ‘Serious Adverse Drug Reactions’, i.e. during clinical investigations, adverse 
events may occur, which if suspected to be medicinal product related (‘adverse drug 
reactions’) might be significant enough to lead to important changes in the way the medicinal 
product is developed (e.g. change in dose, population, monitoring, consent). This is 
particularly true for reactions, which in their most severe form threaten life or function.   
Due to the significant information they provide, Serious Adverse Events (including Serious 
Adverse Drug Reactions) require expedited reporting. SAEs are defined as any adverse event 
or adverse drug reaction which: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization*; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was immediately at risk of death at the time of event; it does not refer to an event, 
which hypothetically might have caused death if it were more severe.  
*An event that results in hospitalisation or prolongs an existing hospitalisation will not be 
considered a serious adverse event if the only reason for the hospitalisation or prolongation 
was: 
• 
Administration of chemotherapy 
• 
Administration of trial procedures 
• 
Placement of a permanent intravenous catheter 
• 
Hospice placement for terminal care 
• 
Pre-trial scheduled elective surgery 
• 
Outpatient hospitalisation for procedures such as: 
 Elective day surgery 
 Convenience purposes (eg. transportation difficulties) 
 Planned admission as part of supportive care for insertion of PEG tube or 
naso-gastric tube for commencement of enteral feeding (i.e. did not occur 
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following urgent admission as a result of weight loss or other patient medical 
events) 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to study treatment that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the BaCT Trial Centre and to Merck. 
SAE reports and any other relevant safety information are to be forwarded within 24 
hours to: 
BaCT Safety:  safety_BaCT@petermac.org     
Merck Global Safety Fax No:  +1-215-993-1220  
ANZUP Safety:  sae.anzup@anzup.org.au  
All participants with serious adverse events must be followed up for outcome. 
 
7.2.5.2 Attribution of Cause of an Adverse Event 
Attribution of cause requires at least a reasonable possibility of a causal relationship between 
the event and the use of a pharmaceutical product (or any other protocol specified 
intervention including radiation therapy, surgery or use of a device), i.e. the relationship 
cannot be ruled out. One or more of the following categories should be attributed as the cause 
of an event:  
• 
Pharmaceutical product (an SAE which is drug related is considered a Serious 
Adverse Drug Reaction) 
• 
Radiation Therapy 
• 
Medical Device 
• 
Surgery 
• 
Unrelated to trial treatment (i.e. progressive disease, concurrent medication, 
concurrent disorder or other  
All protocol specified interventions (including pharmaceutical products, radiation therapy, 
surgery or use of a device) administered prior to the date of the event must be attributed a 
degree of causality from one of the following codes: 
• 
Unrelated 
• 
Unlikely to be related 
• 
Possibly related 
• 
Probably related 
• 
Definitely related 
 
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7.2.5.3 Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event eCRF and reported within 24 
hours to the BaCT Trial Centre, ANZUP and to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220).  
For the time period beginning when the consent form is signed until patient registration, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the BaCT Trial Centre to Merck Global Safety if it causes the subject to be excluded from the 
trial, or is the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not related to 
Pembrolizumab, must be reported within 24 hours to the BaCT and within 24 hours to Merck 
Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of pembrolizumab, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.   
7.2.6 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.03. All adverse events 
regardless of CTCAE grade must also be evaluated for seriousness. Laboratory values need 
reporting as AEs only if abnormal and deemed clinically significant by the investigator. 
7.2.7 Adverse Event Reporting 
All adverse events, which occur whilst the participant is enrolled on the trial, must be 
reported in the patients’ medical records and recorded on the relevant CRF. The Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03) must be used.  
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7.2.8 SAE Reporting 
All serious adverse events (SAEs) that occur from the time a participant signs the consent 
form to within 30 days after the patient has stopped study participation (defined as time 
of last dose of investigational product taken), are required to be reported to the Peter 
MacCallum Centre for Biostatistics and Clinical Trials (BACT), the Sponsor (ANZUP) and 
to Merck Global Safety. Any SAEs experienced after this 30-day period should also be 
reported to BACT only if the investigator suspects a causal relationship to the study 
treatment. 
The Principal Investigator (PI) (or delegate) must: 
• Determine whether an AE is ‘Serious’ (see Section 7.2.6.1)  
• For SAEs, the PI or his/her delegate must assess the relationship to the study drug, then 
ascertain the suspected cause  
• The attribution to the SAE must be recorded in the patients’ medical records and reported 
on the SAE form.  
• The PI or his/her delegate must then determine whether the SAE (or Serious Adverse Drug 
Reaction) is expected or unexpected. 
• Both expected and unexpected Serious Adverse Events and Serious Adverse Drug 
Reactions must be recorded in the patients’ medical records and reported to BaCT and to 
Merck Global Safety. See below for timelines. 
SAEs must be reported by completing the Trial SAE form and emailed/faxed to the 
following: 
 
Send To: 
Contact Details 
Trial Coordinating 
Centre, BaCT 
 
Email:   safety_BaCT@petermac org 
 
Fax:   +61 3 9656 1420 
 
Merck Global Safety 
Attn: Worldwide 
Product Safety;   
Fax:   +1 215 993-1220 
ANZUP Safety 
Email: sae.anzup@anzup.org.au 
 
All SAE must be reported within one working day (24 hours) of becoming aware of the 
event/information (for initial AND for follow-up).  Refer to the table below for further 
details. 
 
 
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Initial Report             
Within one working day (24 hours) of discovery or 
notification of the event.  If the reporting of an SAE is 
delayed, an explanation must be provided in the comments 
section of the SAE form. 
Incomplete Reports*               If all details are not available at the time of the initial report a 
completed report must be sent within the next 8 days.  
Updated/ follow-up Report  
 
If the event is not resolved (or is ‘on-going’) at the time of 
the initial report, the SAE updates need to be submitted to 
BaCT and marked as follow up and provided within one 
working day (24 hours). 
*The Investigator is ultimately responsible for reporting the SAE and must sign the SAE 
report(s). Should this Investigator not be available to sign the initial SAE form within the 24-
hour period, a comment to this effect must be written on the form and the form faxed without 
signature to BaCT and Merck. The investigator must sign the SAE form as soon as possible 
and re-fax to BACT and Merck.  
The Investigator at the Trial Site is responsible for determining the local SAE reporting 
requirements of the responsible HREC and subsequently notifying the HREC of SAEs as 
required.  
 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Follow-up information is sent to BACT as above, using the SAE Report Form stating that 
this is a follow-up to the previously reported SAE and giving the date of the original report. 
The follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the patient continued or withdrew from study 
participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study drug, Merck may urgently require 
further information from the investigator for Health Authority reporting.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected by BaCT and 
the Sponsor and reported to the competent authorities and relevant ethics committees in 
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accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
7.2.9 Sponsor Responsibility for Reporting Adverse Events and Serious Adverse 
Events 
The Sponsor is responsible for: 
• Implementing and maintaining a suitable recording system to record information from 
all SAEs received from Trial Sites. 
• Ensuring that the coordinating principal investigator (CPI) or delegate is notified of 
each SAE to enable the SAE to be assessed by the CPI and any other appropriate 
reviewers for nature (expected/unexpected), causality and whether the TGA needs to 
be notified of the SAE. 
• Under the direction of the CPI or delegate, notifying the TGA (Australia) in 
accordance with the regulatory authority’s detailed guidance of any SUSARs that are 
fatal or life threatening as soon as possible but no later than 7 days after the site 
gained first knowledge of the event. Incomplete reports must be completed and 
forwarded as soon as soon as possible within 8 additional calendar days. All other 
serious, unexpected ADRs should be reported to the TGA within 15 days after the site 
gained first knowledge of the event. 
• Considering information provided by (non-serious) adverse event data. 
• Informing each trial site of new information arising from serious and non-serious 
adverse events and adverse drug reactions that may affect the conduct of the Trial, or 
the rights, interests, safety or wellbeing of Trial Participants. 
• Under the direction of the CPI or delegate, notifying the TGA of any significant issue 
that has arisen from analysis of overseas reports or action that has been taken by 
another country’s regulatory authority within 72 hours of first knowledge. 
• Reporting Serious ADRs to the responsible HREC according to local requirements 
The Investigator at each Trial Site is responsible for reporting Serious ADRs to the 
responsible Research Governance Office (RGO) according to local requirements. 
 
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
This is a single arm study. The primary and secondary objectives for the study will be: 
Primary 
To assess feasibility of pembrolizumab in combination with chemoradiation, as measured by 
a satisfactorily low rate of unacceptable toxicities (UT’s) in the patient sample. A UT is 
defined as occurrence of any one of the following events: 
a) occurrence of a grade 3 or 4 acute AEs (excluding grade 3 or 4 urinary AE), occurring 
either during treatment or within 12 weeks after completion of treatment, or 
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b) Cisplatin being withheld for > 2 doses or any cisplatin dose reductions resulting in 
<66% of the intended total cisplatin dose being delivered, relative to the cisplatin starting 
dose. 
c) Radiation treatment being delayed beyond more than 7 weeks 
d) Any pembrolizumab being delayed for more than 6 weeks (Multiple dose delays will 
not be aggregated). 
Patients will be assessed for acute toxicity at each visit throughout treatment and in follow up 
as outlined in the trial schema. Expected rates of patients experiencing a G3-4 event 
excluding urinary toxicity having chemoradiotherapy without pembrolizumab are between 5-
30% [7, 8, 19]. Grade 3-4 urinary toxicity is a common adverse event experienced during 
chemoradiotherapy occurring in 20% of patients [12] related to radiation related changes to 
the bladder resulting in urinary frequency. Rates of urinary toxicity will be collected during 
the study, but will not contribute to the assessment total of G3-4 events. 
The radiotherapy discontinuation rate has been reported to be between 0-5% [7, 8, 19].  
The experimental regimen would be worthy of further pursuit if safe and feasible to deliver 
to patients without excessive toxicity or modification of radiation or dosage of cisplatin. 
Secondary 
To test for an initial efficacy signal, as measured by the complete response (CR) rate, defined 
as achieving pT0 at either the 1st or 2nd cystoscopic examination. 
Additional secondary objectives are to document (over the 3-5 years of follow up for 
patients) 
- 
overall survival  
- 
metastatic disease-free survival; and  
- 
locoregional progression free survival  
Cystoscopic assessment will be undertaken 12 weeks and 24 weeks after completion of 
chemoradiotherapy. This involves examination under anesthesia, cystoscopy and biopsy of 
all previously positive tumor sites that is utilized to evaluate the tumor status (response) 
following completion of chemoradiotherapy. In some patients radiographic or cystoscopic 
evaluation will reveal abnormalities at the bladder tumor-site (such as thickening of the wall, 
ulcerations, or possible nodularities) which contain no identifiable tumor cells histologically.  
Patients will be considered to have had a complete response, or pT0 response, when: i) the 
bi-manual examination under anesthesia is negative; ii) all the biopsies are negative for any 
tumor at the site(s) of the pretreatment tumor(s) and iii) there is an absence of metastatic 
disease on the most recently performed systemic imaging. 
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8.2 
Sample Size Calculation 
In order to justify continuing to explore pembrolizumab in combination with chemoradiation 
in a larger study, we must establish that the true underlying risk of unacceptable toxicities 
(UT’s) in the population is acceptably low. To this end we need to decide upon values for a 
number of important parameters. Firstly, we need to decide upon a decision threshold for the 
maximum number of UT’s allowable in the study sample before we conclude that the 
regimen is unsafe. In the event that the regimen is concluded to be unsafe, it should either be 
modified upon recommendation of the TMC before being considered further, or abandoned.  
Additionally, we need to define two limits on the true underlying UT rate. The first is a 
“definitely considered safe” limit, defined such that if the true underlying UT rate is at this 
limit (or below) then we want to be confident that our decision threshold on the sample will 
yield a high probability that we will continue into a larger study focused on efficacy. The 
second is a “definitely considered unsafe” limit, defined such that if the true underlying UT 
rate is at this limit (or above) then we want to be very confident that our decision threshold 
on the sample will yield a high probability that we will discontinue – i.e. that we will reject 
the regimen as it currently stands for further consideration, and defer to the TMC for 
direction on whether and how to modify it. 
To further mitigate risk, we would like accrual to proceed in two stages, with an interim 
analysis after the first stage at which stopping will be considered if the early evidence of a 
too high rate of UT’s is convincing. 
Under the proposed design, we desire to constrain the probability of discontinuation if the 
true underlying UT rate is at the definitely considered safe limit to a maximum of 20%, and 
at the same time limit the risk of continuing if the true underlying UT rate is at the definitely 
considered unsafe limit to 10%. We would like to consider the “definitely considered safe” 
rate of UT’s to be 30%, and the “definitely considered unsafe” rate of UT’s to be 50%. 
These goals can be achieved with a sample size of 30 patients. Consider a Simon’s two stage 
design whereby accrual will be halted if we see greater than 5 UT’s amongst the first 10 
patients and greater than 11 amongst the first 30 patients. Given these stopping thresholds, if 
the true underlying UT rate is 0.3 then the cumulative probability of concluding unsafe after 
stage 2 of accrual will be 17% and if the true underlying rate of UT is 0.5 then the cumulative 
probability of concluding unsafe after stage 2 of accrual will be 90%. The relationship 
between the true underlying UT rate and the probability of concluding unsafe is shown in 
Figure 2. 
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Figure 2: Probability of concluding unsafe as a function of true underlying UT rate 
As a secondary objective, we desire to test for an initial signal of efficacy by estimating the 
proportion of patients achieving a best response of complete response (CR). (See sections 3.2 
and 7.1.2.6.2 for the definition of best response.) Similar to the procedure for placing 
thresholds on the number of UT’s we define a threshold for the minimum number of CR’s 
that must be seen in the sample in order to consider the regimen worthy of further 
investigation on the basis of efficacy. We also define a “maximum uninteresting” true 
underlying CR rate – the true underlying CR rate at or below which we would not consider 
the regimen clinically worthy of implementation, and a “minimum interesting” true 
underlying CR rate – the true underlying CR rate at or above which we would consider the 
regimen clinically worthy of implementation. We define the maximum uninteresting and the 
minimum uninteresting rates as being 0.5 and 0.7 respectively. If we place the decision 
threshold at 18 CR’s out of 30, then the probability of judging the regimen worthy of further 
investigation for efficacy if the true underlying CR rate is 0.5 is 10%, and the probability of 
judging the regimen worthy of further investigation for efficacy if the true underlying CR 
rate is 0.7 is 84%. This is illustrated in Figure 3. 
 
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
True underlying UT rate
Probability of concluding u
concluding unsafe based on # of U
( concluding unsafe  if > 5 UT 's in 1st 10 or <= 5 in 1st 1
0.3
0.5
Defin
Defin
Prob. of concluding unsafe after 10 patients
Prob. of concluding unsafe after 30 patients
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Figure 3: Probability of further investigation as a function of true underlying CR rate. 
8.3 
Methods of analysis 
Binary proportions (UT and CR proportions) and their 95% CI’s will be provided using the 
Clopper-Pearson method. Table 10 provides estimates and 95% CI’s for various observed 
counts from a sample size of 30. 
Table 10: Estimated proportions and corresponding 95% CI’s for a sample size of 30. 
Count 
Estimate 
95% CI 
3 
0.1 
[0.02, 0.27] 
6 
0.2 
[0.08, 0.39] 
9 
0.3 
[0.15, 0.49] 
12 
0.4 
[0.23, 0.59] 
15 
0.5 
[0.31, 0.69] 
18 
0.6 
[0.41, 0.77] 
21 
0.7 
[0.51, 0.85] 
24 
0.8 
[0.61, 0.92] 
27 
0.9 
[0.73, 0.98] 
 
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When estimating the UT rate and its 95% CI, the methods of Jung & Kim (2004) and 
Koyama & Chen (2008) will be used to adjust for the two stage sampling procedure. 
It is expected that it will take two years to accrue the required 30 patients. Accrual will not be 
suspended pending the results of the interim analysis. 
OS, DMFS and LRPFS will be characterized using Kaplan-Meier curves.  
Both DMFS and LRPFS will be measured from the date of patient registration. DMFS will 
be measured until the date of first commencement of any non-protocol anti-cancer therapy, 
detection of distant metastasis, or death due to any cause. LRPFS will be measured until the 
date of first commencement of any non-protocol anti-cancer therapy, detection of local or 
regional progression, or death due to any cause. Occurrence of distant metastasis will be a 
censoring event for measurement of LRPFS. There are no censoring events for DMFS. 
8.4 
Exploratory analysis 
Tissue, blood and urine will be collected for biomarker analysis as part of the study. 
Requirements for biomarkers analysis are described in PCR-MIB Biomarker Laboratory 
Manual. 
Resected tumour specimens will be available from the patients enrolled on the trial.  These 
pre-treatment specimens will be comprehensively profiled for the abundance and 
composition of tumour infiltrating lymphocytes (CD4, CD8, CD3, CD20 and FoxP3 positive 
cells) by immunohistochemistry using the state-of-the-art Vectra Automated Imaging system 
recently acquired by the ONJCRI which enables multiplexed immunohistochemical analysis. 
Descriptive statistics will quantify individual immune parameters and correlation with 
response.  
Blood samples collected prior to treatment, at the end of chemoradiotherapy, and after 24 
weeks will be collected from the patients on the trial. PBMCs will be isolated using Ficoll, 
and changes in specific immune subpopulations (number/ratio) determined by multi-
parameter FACS. Changes in the immune regulatory molecules OX-40/LAG3/PD1/ICOS on 
T cell subsets will be assessed by flow cytometry. Descriptive statistics will quantify 
individual immune parameters and correlation with response.  
Changes in gene expression in CD3+ cells pre and post-treatment will be determined by 
RNAseq analysis to assess for gene expression changes associated with immune activation 
[9]. Descriptive statistics will quantify individual immune parameters and correlation with 
response.  
Finally, to independently monitor B cell responses, pre- and post-treatment serum samples 
from the 30 trial patients will be analysed using CT100 microarrays for changes in titres of 
100 cancer-testis auto-antibodies  [10]. Descriptive statistics will quantify individual immune 
parameters and correlation with response.  
 
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Other immune endpoints potentially measurable using the biomarker resources from the trial 
include but not are not limited to circulating DNA, antibody titres, peripheral blood markers 
of immune change and urine detectable immunological markers. 
8.5 
Timing of Analyses 
A total of three analyses will be performed.  
1. The interim analysis for the primary objective (feasibility) will take place after the 
10th patient has reached the 31 week assessment time point. 
2. Provided that the interim analysis does not result in the trial being closed prematurely 
due to unacceptable toxicity, the final analysis for the primary objective will take 
place after the last patient has reached the 31 week assessment time point. 
3. Provided that the interim analysis does not result in the trial being closed prematurely 
due to unacceptable toxicity, the analysis for the secondary efficacy objectives, as 
well as the analysis of any exploratory objectives, will take place after the last patient 
has reached 3 years past registration. 
 
9.0 SAFETY PARAMETERS/REVIEW AND MODIFICATIONS TO TRIAL 
Given the experimental nature of the addition of pembrolizumab to concurrent 
chemoradiation, the following safety measures will exist 
1) The trial operations executive (TOE) and the trial management committee (TMC) 
will review safety issues related to the trial through regular teleconferences held 
throughout the trial.  
2) An additional safety review by the TMC will take place 12 weeks after completion of 
treatment for the 10th patient whereby accrual will be halted if we see greater than 5 
UT’s amongst the first 10 patients recruited using the Simon’s two stage design 
described above in 8.2. Accrual can continue until the results of the interim analysis 
are available to the TMC.  
3) Modifications to trial 
a. Based on safety discussion the TMC may recommend to either 
i. Omit concurrent pembrolizumab with chemoradiotherapy, and give 
pembrolizumab 200mg IV q3 weekly at week 7, 10, 13, 16 and 19 
alone 
ii. Modify the chemotherapy arm to allow either carboplatin, or 
5FU/MMC [8] 
iii. Suspend the study 
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iv. Any other modification suggested to reduce toxicity made by the TMC 
The enrolment to the trial will be monitored by theTMC and if enrolment is reduced due to 
concerns regarding design of the trial, the TMC will suggest modifications that may include 
modification of the chemotherapy arm to allow concurrent carboplatin or 5FU/MMC. 
 
10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
10.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. Detailed description is in the Pharmacy Manual. 
Clinical Supplies will be provided by Merck and distributed by the central pharmacy are 
summarized in Table 11. 
Table 11 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
10.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
10.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
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10.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the distribution central pharmacy, the amount dispensed to and returned by the 
participants and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
11.0 STUDY COMMITTEES 
11.1 Trial Management Committee 
This study is conducted by the Australian and New Zealand Urogenital and Prostate Cancer 
Trials Group (ANZUP) in collaboration with the Centre for Biostatistics and Clinical Trials 
(BaCT) who will coordinate this study  
Study coordination, data acquisition and management and statistical analysis will be 
performed by the Centre for Biostatistics and Clinical Trials at Peter Mac.  
The Trial Management Committee (TMC) will oversee study planning, monitoring, progress, 
review of information from related research, and implementation of recommendations from 
other study committees and external bodies (e.g. ethics committees).  
The TMC will consider whether to continue the study as planned, modify, or stop it, based on 
reports provided by the BaCT or other information. 
 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Confidentiality 
The study will be conducted in accordance with applicable Privacy Acts and Regulations. All 
data generated in this study will remain confidential. All information will be stored securely 
at the participating trial sites and at the Centre for Biostatistics and Clinical Trials at Peter 
Mac, U and will only be available to people directly involved with the study and who have 
signed a Confidentiality Agreement. 
12.2 Protocol Amendments 
Changes and amendments to the protocol and patient information and consent form (PICF) 
can only be made by the Sponsor and/or its delegate. Approval of amendments by the 
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Institutional HREC is required prior to their implementation. In some instances, an 
amendment may require a change to a consent form. The Investigator must receive 
approval/advice of the revised consent form prior to implementation of the change. In 
addition, changes to the data collected, if required, will be incorporated in the amendment.  
The investigator should not implement any changes to, or deviations from, the protocol 
except where necessary to eliminate immediate hazard(s) to trial subject(s). 
12.3 Data Handling and Record Keeping 
All trial data required for the monitoring and analysis of the study will be recorded 
electronically on the Electronic Data Capture e-sytem provided by the Centre of Biostatistics 
and Clinical Trials. All required data entry fields must be completed. Data corrections will be 
done according to the instructions provided. Site investigator’s will be asked to confirm the 
accuracy of completed eCRFs by signing key eCRFs as indicated.  
Source documents pertaining to the trial must be maintained by investigational sites and 
copies provided to BaCT when requested. Source documents may include a subject's medical 
records, hospital charts, clinic charts, the investigator's subject study files, as well as the 
results of diagnostic tests such as X-rays, laboratory tests, and electrocardiograms. The 
investigator's copy of the case report forms serves as part of the investigator's record of a 
subject's study-related data.  
The following information should be entered into the subject's medical record:  
a. Subject’s name, contact information and protocol identification.  
b. The date that the subject entered the study, and subject number.  
c. A statement that informed consent was obtained (including the date).  
d. Relevant medical history  
e. Dates of all subject visits and results of key trial parameters.  
f. Occurrence and status of any adverse events.  
g. The date the subject exited the study, and a notation as to whether the subject completed 
the study or reason for discontinuation. 
All study-related documentation at ANZ sites will be maintained for 25 years following 
completion of the study. 
12.4 Compliance with Trial Registration and Results Posting Requirements 
This study will be conducted according to the Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration 
DSEB July 2000) and in compliance with applicable laws and regulations. The study will be 
performed in accordance with the NHMRC Statement on Ethical Conduct in Research 
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Involving Humans (© Commonwealth of Australia 2007), and the NHMRC Australian Code 
for the Responsible Conduct of Research (©Australian Government 2007), and the principles 
laid down by the World Medical Assembly in the Declaration of Helsinki 2008. To this end, 
no participant will be recruited to the study until all the necessary approvals have been 
obtained and the participant has provided written informed consent. Further, the investigator 
shall comply with the protocol, except when a protocol deviation is required to eliminate 
immediate hazard to a subject. In this circumstance the coordinating center, principal 
investigator and HREC must be advised immediately. 
The sponsor will ensure that information on the trial is listed through the Clinical Trials Data 
Bank, http://www.clinicaltrials.gov.   
12.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial. 
 
12.6 Audit and Inspection 
This study may be subject to audit or inspection by representatives of the collaborative group 
or the Centre for Biostatistics and Clinical Trials (BaCT) or representatives of regulatory 
bodies (e.g. Therapeutic Goods Administration (TGA)), US Food and Drug Administration 
(FDA)). 
12.7 Statistical Report 
A Statistical Report which summarises and interprets all the pertinent study data collected 
will be issued which may form the basis of a manuscript intended for publication. The 
Statistical Report or summary thereof will be provided to the study investigators, ANZUP 
and the ethics committees. 
12.8 Publication Policy 
Authorship recognises the intellectual contributions of investigators and others to a study. It 
also identifies those who take public responsibility for the study. Authorship is defined as per 
ICMJE guidelines (www.icmje.org). The Trial Management Committee will appoint a 
Writing Committee to draft manuscript(s) based on the trial data. The Writing Committee 
will develop a publication plan, including authorship, target journals, and expected dates of 
publication. The first publication will be the report of the full trial results based on the main 
protocol using the study group name with a list of specific contributions at the end. ANZUP 
will be acknowledged in all publications. All publications must receive prior written approval 
from the TMC prior to submission  
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13.0 APPENDICES 
13.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
13.2 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
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Sabaa, M.A., et al. Combined modality treatment with bladder preservation for 
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James, N.D., et al., Radiotherapy with or without chemotherapy in muscle-invasive 
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16. 
Giaccone, G., et al., Safety, activity and biomarkers of atezolizumab (MPDL3280A) 
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Papadimitrakopoulou, V., et al., Pembrolizumab (pembro; MK-3475) plus platinum 
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