A Phase II Trial of Combination Cabazitaxel and Cisplatin Chemotherapy in the Neo-adjuvant Treatment of Transitional Cell Carcinoma of the Urinary Bladder
Phase: PHASE2
Conditions: Infiltrating Bladder Urothelial Carcinoma
Sponsor: University Hospitals Bristol and Weston NHS Foundation Trust

 
 
NCT01616875 
 
A Phase II Trial of Combination 
Cabazitaxel and Cisplatin 
Chemotherapy in the Neoadjuvant 
Treatment of Transitional Cell 
Carcinoma of the Urinary Bladder 
 
Bristol Bladder Trial 
 
Protocol version 8.0  
 
Dated   01/03/2017 
 
 
This protocol is a controlled document and should not be copied, 
distributed or reproduced without permission

 
Bristol Bladder Trial Protocol  Version 8.0   01/03/17  
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Bristol Bladder Trial Protocol  Version 8.0   01/03/17  
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Chief Investigator  
Prof Amit Bahl 
 
Sponsor 
 University Hospitals Bristol and Weston NHS Foundation Trust 
(UHBW) 
 
Funder 
 
 
Aventis Pharmaceuticals Ltd. (trading as ‘Sanofi’) 
 
Coordinating Unit  
Bristol Haematology and Oncology Centre 
 
 
 
 
Clinical Trials Unit 
 
REC reference number  
11/SW/0345 
 
UHBW reference  
 
ON/2011/3775 
 
Funder’s reference 
 
Cbzl06112 
 
EudraCT number  
 
2011-004090-82 
 
Administration 
Clinical Co-ordination:  
Profr Amit Bahl, Consultant Clinical Oncologist (Chief Investigator)  
Bristol Haematology & Oncology Centre  
Horfield Road  
Bristol, BS2 8ED  
Tel: 0117 342 2418  
E-mail: amit.bahl@uhbristol.nhs.uk 
 
Dr Susan Masson  
Consultant Clinical Oncologist  
Bristol Haematology & Oncology Centre  
Horfield Road  
Bristol,BS2 8ED  
Tel: 0117 342 2418 
E-mail: susan.masson@uhbristol.nhs.uk 
 
Protocol Development Group 
 
Prof Amit Bahl 
 
Chief Investigator  
 
Dr Susan Masson    
Co-Chief-Investigator 
 
Miss Sylvia Pearson 
Study manager, Bristol Haematology & Oncology Centre 
 
 
 
 
 
Dr Rosemary Greenwood  Independent Medical Statistician 
 
Dr Julian Kabala  
 
Consultant Radiologist 
(DCE MRI substudy) 
University Hospitals Bristol and Weston NHS Foundation Trust 
 
Dr Janice Ash-Miles  
Consultant Radiologist 
(DCE MRI substudy) 
North Bristol NHS trust 

 
Bristol Bladder Trial Protocol  Version 8.0   01/03/17  
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This protocol describes the Bristol Bladder Trial and provides information about proce-
dures for entering and treating patients. The protocol should not be used as a guide for the 
treatment of other patients; every care was taken in its preparation, but corrections or 
amendments may be necessary. These will be circulated to investigators in the trial, but 
centres entering patients for the first time are advised to contact University Hospitals Bris-
tol NHS Foundation Trust to confirm they have the most recent version. Protocol amend-
ments will be circulated to participating centres as they occur.  
 
This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical 
Trials) Regulations 2004 (SI 2004/1031). It will be conducted in compliance with the 
protocol, the Data Protection Act 1998 and other regulatory requirements as appropriate. 
 
 
Protocol Authorised By: 
 
 
 
………………………………………………. 
 
Prof Amit Bahl (Chief Investigator) 
 
 
Date.........................................................

 
Bristol Bladder Trial Protocol  Version 8.0   01/03/17  
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CONTENTS 
 
1 
BACKGROUND.................................................................................... 
1 
2 
AIMS OF THE STUDY........................................................................... 
4 
2.1 
Primary.................................................................................................... 
4 
2.2 
Secondary................................................................................................ 
4 
3 
TRIAL DESIGN..................................................................................... 
4 
4 
PATIENT SELECTION AND ELIGIBILITY.................................................. 
4 
4.1 
Source of Patients.................................................................................... 
4 
4.2 
Number of Patients.................................................................................. 
4 
4.3 
Inclusion Criteria...................................................................................... 
5 
4.4 
Exclusion Criteria..................................................................................... 
5 
5 
ENDPOINTS......................................................................................... 6 
5.1 
Primary.................................................................................................... 
6 
5.2 
Secondary................................................................................................ 
6 
5.3 
Definition and Recording of response and disease progression.............. 
7 
6 
REGISTRATION.................................................................................... 
8 
7 
TRIAL EVALUATIONS........................................................................... 
8 
7.1 
Baseline.................................................................................................... 8 
7.2 
On treatment assessments...................................................................... 
9 
7.3 
End of chemotherapy treatment............................................................. 
9 
7.4 
Radical cystectomy.................................................................................. 
9 
7.5 
Long term follow up................................................................................. 
10 
7.6 
Qualitative data....................................................................................... 
10 
7.7 
Schema of trial evaluations...................................................................... 11 
8 
TRIAL TREATMENT.............................................................................. 
13 
8.1 
Drug supplies and labelling...................................................................... 
13 
8.2 
Pre-medication........................................................................................ 
14 
8.3 
Anti-emetics............................................................................................. 14 
8.4 
Guidelines for the management of toxicity............................................. 
15 
8.5 
Dose modifications and delays................................................................ 
17 
8.6 
Concomitant medications……………………………………………………………………. 
19 
8.7 
Contraception……………………………………………………………………………………… 
19 
9 
SAFETY AND PHARMACOVIGILANCE................................................... 
19 
9.1 
Definitions................................................................................................ 19 
9.1.1 
Adverse events (AEs)............................................................................... 
19 
9.1.2 
Serious adverse events (SAEs)................................................................. 
19 
9.1.3 
Serious adverse reactions (SARs)............................................................. 
20 
9.1.4 
Suspected unexpected serious adverse reactions (SUSARs)................... 
20 
9.2 
Causality (relatedness)............................................................................. 20 
9.3 
Procedure for collecting adverse events................................................. 
21 
9.4  
Procedure for recording serious adverse events/reactions..................... 
21 
9.5 
Reporting of serious adverse events/reactions to the sponsor............... 
21 
9.6 
Review of serious adverse events/reactions............................................ 21 
9.7 
Expedited reporting of SUSARs................................................................ 
21 
9.8 
Follow-up of serious adverse events/reactions....................................... 
22 
9.9 
Annual reporting of serious adverse events/reactions............................ 
22 
10 
FURTHER MANAGEMENT AT THE END OF STUDY TREATMENT............. 
23 
11 
STATISTICAL CONSIDERATIONS............................................................ 
23 
11.1 
Choice of principal endpoints.................................................................. 
23 
11.2 
Sample size calculations........................................................................... 23 
11.3 
Stopping rules…………………………………………………………………………………….. 
23 

 
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11.4 
Analysis methods..................................................................................... 
24 
11.4.1 
Primary endpoint..................................................................................... 
24 
11.4.2 
Secondary endpoints............................................................................... 
24 
11.4.3 
Missing data............................................................................................. 
25 
11.5 
Frequency of analyses.............................................................................. 25 
12 
RESEARCH GOVERNANCE.................................................................... 
25 
12.1 
Trial administration.................................................................................. 
25 
12.1.1 
Responsibilities........................................................................................ 
26 
12.2 
Protocol compliance and initiation.......................................................... 
27 
12.3 
Data acquisition and on-site monitoring................................................. 
27 
12.4 
Archiving.................................................................................................. 
27 
12.5 
Data Protection Act.................................................................................. 27 
13 
TRIAL MANAGEMENT.......................................................................... 28 
13.1 
Trial Management Group......................................................................... 
28 
13.2 
Trial Steering Committee......................................................................... 
28 
13.3 
Data Monitoring ommittee.................................................................... 
28 
14 
END OF STUDY.................................................................................... 
28 
15 
PUBLISHING POLICY............................................................................ 
29 
16 
CONFIDENTIALITY AND LIABILITY........................................................ 
29 
16.1 
Risk assessment....................................................................................... 
29 
16.2 
Liability/indemnity/insurance.................................................................. 29 
16.3 
Patient Confidentiality............................................................................. 
29 
17 
ETHICAL CONSIDERATIONS................................................................. 
30 
18  
WITHDRAWAL OF PATIENTS................................................................ 
30 
18.1 
Withdrawal of patients from trial treatment........................................... 
30 
18.2 
Withdrawal of patients from trial follow up............................................ 
31 
19 
FINANCIAL MATTERS........................................................................... 32 
20 
ASSOCIATED STUDIES.......................................................................... 32 
20.1 
DCE MRI Substudy.................................................................................... 
32 
20.2 
CTC Substudy............................................................................................ 32 
 
REFERENCES....................................................................................... 
33 
 
 
 
 
 
 
 
 
 
APPENDIX 1: RECIST Criteria version 1.1....................................................................... 
R1-R7 
APPENDIX2: 
Measurement of GFR............................................................................... 
G1 
APPENDIX 3: Study Drug (Cabazitaxel) product information and handling………………… S1-S3 
APPENDIX 4: Quality of Life Questionnaires QLQ C30, module BLM-30 and EQ5D……. 
Q1-Q8 
APPENDIX 5: 
 
CYP3A inducers + inhibitors…………………………………………………………………   
…………………………………….. 
Y1-Y2 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

 
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TRIAL SCHEMA 
 
Patient with Invasive Primary 
transitional cell carcinoma of the 
urinary bladder 
Patient deemed fit to receive 
neoadjuvant chemotherapy and 
undergo radical cystectomy 
Disease defined as: 
 
• 
Histologically proven invasive transitional 
cell carcinoma of the urinary bladder 
 
• 
Stage: 
T2-T4a  
N0, M0 determined by CT imaging 
Patient registered in the trial to receive 4 cycles 
combination chemotherapy with Cabazitaxel and 
Cisplatin 
 
• 
CT Chest, Abdomen and Pelvis and 
cystoscopy after 3 cycles 
chemotherapy (as per current 
standard) 
DCE MRI 
pelvis prior to 
chemotherapy 
and after first 
and third 
cycles 
(Appendix 1) 
Patient has radical cystectomy 
and pathological response to 
chemotherapy is recorded 
Optional substudies: 
Patient with invasive primary 
transitional cell carcinoma of the 
urinary bladder 
CTC 
measurement 
prior to each 
chemotherapy 
cycle and 
prior to 
surgery 
(Appendix 2) 
CTC 
measurement 
after surgery 
(Appendix 2) 

 
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TRIAL SUMMARY 
 
Title  
A phase II trial of combination cabazitaxel and cisplatin in 
the neoadjuvant treatment of transitional cell carcinoma of 
the urinary bladder 
 
Objectives 
Primary:  
 
To evaluate the overall response rate with this chemothera-
py regimen in the neoadjuvant treatment of transitional cell 
carcinoma of the bladder and thus determine whether this 
approach warrants further research (randomised Phase II/ III 
trial). 
 
 
 
 
 
 
Secondary: 
• 
To evaluate safety and tolerability; 
• 
To assess progression-free and overall survival; 
• 
To assess quality of life during treatment. 
 
Trial Design  
 
 
 
 
Non-randomised single centre trial 
 
Type and number of patients  
Patients with invasive transitional cell carcinoma of the blad-
der will be eligible if they are fit to receive chemotherapy as 
neoadjuvant treatment and to undergo a radical cystectomy. 
 
Approximately 26 patients will be recruited. 
 
Treatment 
Four cycles of chemotherapy using a combination regimen 
comprising: 
 
Cabazitaxel 15 mg/m2 day 1 + cisplatin 70mg/ m2 day 1. The 
combination treatment is prescribed every 21 days.  
 
 
Endpoints  
 
 
 
 
Primary: The primary endpoint is overall response rate 
(complete remission rate + partial remission rate) deter-
mined by histopathological staging at cystectomy. 
 
Secondary:  
• 
Progression-free survival; 
• 
Overall Survival; 
• 
Acute toxicity (CTCAE v4.03) after each cycle ; 
• 
Quality of life (assessed by EQ5D and EORTC 
QLQ-C30 and module BLM-30) 
 
Associated Studies 
Patients with no contraindications to MRI or gadolinium 
contrast may enter an optional substudy evaluating dynamic 
contrast enhanced MRI prior to therapy, and after one and 
three cycles of chemotherapy. 
 
 
 
 
 
 
 
Patients will be offered entry into an optional pilot substudy 
involving measurement of circulating tumour cell (CTC) 
concentration prior to each cycle of chemotherapy and prior 
to surgery. 
 

 
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1 
BACKGROUND 
 
Carcinoma of the urinary bladder is the seventh most common cancer in the United 
Kingdom, (1) (2) (3) (4) with around 10,000 diagnoses annually.  The majority of these are 
transitional cell carcinoma (TCC).   30% of cases present with disease invading into the 
muscle wall of the bladder (tumour stage T2 or greater) and a further 50% of patients 
presenting with high risk non muscle invasive (superficial) bladder cancers will later 
develop muscle invasive disease.   
5 year survival after cystectomy for patients with muscle invasive bladder cancer varies 
from 36% to 48%, and specifically 17% to 46% for pT3b tumours. (5) Many patients die 
from metastatic disease.  Tumour (T) stage at diagnosis is a key prognostic factor, and so 
accurate staging at diagnosis is an important requirement.  Other influential factors are 
tumour grade, presence or absence of multiple tumour foci, and tumour type.   
In the absence of lymph node or distant metastases, patients with T2 to T4a disease who 
have adequate performance status and organ function are typically treated with first line 
combination chemotherapy, using a cisplatin-based regimen, followed by radical cystec-
tomy as the current standard of care.  The use of neoadjuvant chemotherapy is supported 
by data from two large meta-analyses, (6) (7) (8) incorporating a total of 11 individual ran-
domised trials of over 3000 patients, demonstrating a significant overall survival advantage 
with this approach when compared with local treatment (cystectomy or radiotherapy) 
alone.   
The ABC meta-analysis (6) (7) represented 98% of all published relevant randomised con-
trolled trials. Although there were several inter-trial differences, results indicated an abso-
lute improvement of 5% in overall survival, 14% decrease in disease specific mortality and 
9% improvement in disease specific survival with chemotherapy in patients of good per-
formance status.   
Furthermore the largest BA06 trial of 970 patients, comparing no neoadjuvant therapy to 3 
cycles of CMV (cisplatin, methotrexate and vinblastine) has demonstrated an improvement 
in 10 year overall survival from 30% to 36% with chemotherapy. The choice of neoadjuvant 
chemotherapy agents is guided by the larger individual trials.  
 
The phase III SWOG 8710 (Intergroup 0080) trial, (9) comparing neoadjuvant MVAC 
(methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy and cystectomy with 
cystectomy alone, played a pivotal role. 5 year overall survival favoured chemotherapy 
(57% vs. 42%), and was 85% in patients who had a pathological complete response.  
Although the strength of the study design is debated (10) (11), particularly the statistical 
methods and the duration of the trial, neoadjuvant chemotherapy with MVAC has been 
increasingly prescribed since its publication, particularly in the USA.     
However, MVAC itself is somewhat toxic. The incidence of grade 4 granulocytopenia in the 
above trial was 33% and GI complications 29%.  
A historical control series evaluated the efficacy of neoadjuvant gemcitabine plus cisplatin 
(GC) compared with MVAC in muscle invasive urothelial cancer of the bladder. (12) Earlier 
work had shown GC to be less toxic with similar response and survival rates compared 
with MVAC in advanced disease. (13) (14) Notably, however, no phase III ‘head to head’ 
trial has compared MVAC with GC in the neoadjuvant setting, and this trial will probably 
never now occur.  

 
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The common factor to positive trial results in this setting is the use of platinum, specifically 
cisplatin, in combination with other agents. (6) (7) (8)  
Interest in taxanes in the management of invasive bladder cancer has emerged from trials 
in the advanced setting, following failure of platinum-based chemotherapy. (15) (16) (17) 
(18) Encouraging response rates are seen with paclitaxel and docetaxel in metastatic 
disease, and taxanes have also been evaluated in neoadjuvant studies in combination with 
cisplatin prior to chemoradiotherapy or surgery with success. (19) (20) (21) However, as 
with MVAC, toxicity remains a concern, highlighting the importance of patient selection.   
 
Cabazitaxel (Jevtana®, Sanofi-Aventis) is a novel taxoid that was selected for clinical 
development based on its pharmacological profile. (22)  It is effective in cell lines sensitive 
and resistant to docetaxel, vinca alkaloids and anthracylines, and shows activity against 
intracranial tumours. Early pharmacokinetic work shows that cabazitaxel exhibits dose-
proportional PK, a triphasic elimination profile, a long terminal half life (77.3 hrs), a high 
plasma clearance (mean CL 53.5 L/h), a long T ½, and a very large volume of distribution 
at steady state (mean Vss 2,034L/m2). (23) 
Although major trials with cabazitaxel have primarily employed single agent treatment, 
benefit has been seen in combination with other cytotoxic agents in the treatment of meta-
static breast cancer, and it is well tolerated (24).  Recent work in animal models (25)  re-
ports synergism when cabazitaxel is combined with cisplatin.  Data from phase I studies 
using cabazitaxel combined with cisplatin are emerging. (26) 
The putative mechanism for the survival advantage seen with neoadjuvant chemotherapy 
is the early treatment of micrometastatic disease.  However, additional benefits of this 
approach include the potential for local downstaging with surgical bladder preservation 
(partial cystectomy with or without combined radiotherapy), (27) and the ability to assess 
pathological response to chemotherapy.  The former may afford patients a better quality of 
life, as a result of reduced need for extensive surgery and urinary diversion with a lower 
risk of sexual dysfunction.  The routine practice of bladder preservation is yet to become 
commonplace, however; radical cystectomy remains the gold standard.   
 
Typically, response to neoadjuvant chemotherapy is assessed preoperatively, after 3 or 4 
cycles of combination chemotherapy, by clinical assessment, CT imaging and cystoscopic 
examination with or without biopsy, to record response to chemotherapy and exclude 
progression to lymph node or distant metastatic disease.  This, however, is not a substitute 
for the assessment of pathological response obtained at cystectomy, which itself holds 
important prognostic value. (28; 29) 
 
Magnetic resonance imaging (MRI) has been used to evaluate T stage at diagnosis in this 
condition and interest in its use was first described more than 20 years ago (30).  Whereas 
initial studies showed the value of MRI to be limited, the evolution of this modality and 
specifically developments in functional MR imaging, such as dynamic contrast enhanced 
and diffusion weighted techniques (31), have led to renewed enthusiasm for its application 
in bladder cancer diagnosis and assessment of response to treatment.   
 
Several studies (32) (33) (34) have demonstrated improved accuracy, specificity and 
sensitivity for staging bladder cancers when dynamic contrast enhanced techniques are 
performed in addition to unenhanced scans at diagnosis and after irradiation of the 
bladder, as these techniques allow assessment of tumour vascularisation,  as well as 
tumour size and estimated depth of invasion. (35)   Results from diagnostic dynamic MRI 

 
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scans have been shown to correlate with pathological grade and microvessel density on 
transurethral resection (diagnostic) specimens. (32) Furthermore, a Dutch study of 36 
patients with metastatic or locally advanced disease receiving palliative chemotherapy (36) 
demonstrated that dynamic contrast-enhanced MRI may be used to predict failure of 
chemotherapy early in its course, sparing some patients toxicity from ineffective treatment.   
 
 
The use of a single noninvasive imaging technique for this assessment of response has 
clear advantages in terms of patient experience and cost to institutions.  In addition, 
assessment or prediction of response to chemotherapy earlier in its course would 
potentially allow for more individualised therapy; for example early cystectomy or radical 
radiotherapy in patients not responding to neoadjuvant chemotherapy.  There are also 
implications for the use of concurrent chemoradiotherapy, an emerging modality in this 
area, (37) and even image-adapted radiotherapy (38) for non-surgical patients.   
 
 
This Phase II study will serve to establish the response rate to combination cabazitaxel 
and cisplatin chemotherapy in patients with muscle invasive transitional cell carcinoma of 
the urinary bladder, and will evaluate survival and quality of life from this novel approach. 
 
Via a concurrent optional substudy, response to chemotherapy will be assessed using 
standard techniques, with the addition of dynamic contrast enhanced MRI (DCE MRI) at 
diagnosis and after one and three cycles of chemotherapy, to evaluate DCE MRI in the 
early prediction of failure of neoadjuvant chemotherapy.  This study is outlined in a 
separate protocol. 
 
An additional substudy in selected patients will measure circulating tumour cell (CTC) 
concentrations prior to each cycle of chemotherapy and prior to and after surgery, to 
determine whether there is any relationship between CTC concentration and response to 
radical treatment. This is also outlined in a separate protocol.  
 
 

 
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2 
AIMS OF THE STUDY 
 
2.1 
Primary  
To evaluate overall pathological response rate with a combination regimen using 
cabazitaxel and cisplatin in the neoadjuvant treatment of transitional cell carcinoma 
of the urinary bladder, thus determining whether this approach warrants further 
research within the context of a phase III clinical trial. 
 
2.2 
Secondary 
• To evaluate safety and tolerability 
• To assess progression-free and overall survival 
• To assess quality of life during treatment 
 
3 
TRIAL DESIGN 
 
This study is not randomised.  This is a limited phase II study to determine the 
pathological response rate and tolerability of this regimen.   
 
Patients will receive cabazitaxel 15mg/m2 with cisplatin 70mg/m2 day 1.  Cycles last 
21 days and a total of 4 cycles will be given to each patient, with standard workup 
for radical cystectomy including formal re-staging with CT imaging and cystoscopy 
after 3 cycles of chemotherapy. 
 
Patients who have no contraindications to contrast enhanced MRI will be offered 
entry into the associated dynamic contrast enhanced MRI study and will undergo 
DCE MRI scanning prior to cycle 1 and after cycles 1 and 3.   
 
All patients will be asked to provide blood samples for circulating tumour cell (CTC) 
measurement prior to each cycle of chemotherapy and prior to surgery.  
Participation in this CTC substudy is not mandatory. 
 
 
4 
PATIENT SELECTION AND ELIGIBILITY 
 
4.1  
Source of patients  
 
 
Patients undergoing radical treatment for bladder cancer must be managed under 
the auspices of a multidisciplinary team (MDT) whose core members must include a 
consultant oncologist, consultant urological surgeon, consultant radiologist and 
consultant histopathologist. 
 
Patients will be eligible if they have histopathologically confirmed muscle invasive 
primary transitional cell carcinoma of the urinary bladder, are fit to receive 
neoadjuvant combination cabazitaxel and cisplatin chemotherapy, and are fit to 
undergo radical cystectomy.   
 
4.2 
Number of patients 
 
 
Based on previous studies in this disease, an overall response rate of less than 
 
35% (partial or complete remission at cystectomy) would not be sufficient to warrant 
 
further investigation of this approach.  An overall response rate of 60% or higher 
 
would warrant further investigation.   

 
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Using a one-sided confidence interval of 95% and 80% power, a total of 26 patients 
 
are required.  It is anticipated that up to 30 patients will be required to allow for lost 
 
data and patient withdrawals.   
 
 
4.3 
Inclusion Criteria 
• 
Age ≥18 years 
• 
Histologically confirmed primary TCC of the urinary bladder 
• 
T2 to T4 disease, N0 M0 determined by CT imaging and biopsy or transurethral 
resection 
• 
ECOG Performance status 0 or 1 
• 
GFR≥60 mls/min. GFR to be assessed according to local practice. 
Recommended technique of eGFR using the CKD-EPI formula (Appendix 
2). 
• 
 
• 
If the baseline eGFR is 50 - <60 mls/min patient should undergo formal 
testing with measurement of 51 Cr-EDTA clearance. 
• 
 
• 
If the EDTA result is ≥ 60 mls/min the patient is eligible 
• 
If the EDTA result is ≥ 55 mls/min - < 60 mls/min discuss with CI 
• 
If the EDTA result is < 55mls/min patient is excluded from the study. 
 
• 
Written, informed consent 
 
4.4 
Exclusion Criteria 
• 
ECOG Performance Status ≥ 2 
• 
Lymph node involvement or metastatic disease 
• 
Prior surgery (except transurethral resection of bladder tumour), radiation, 
chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrolment  
• 
Active Grade ≥2 peripheral neuropathy 
• 
Active secondary cancers  
• 
History of severe hypersensitivity reaction (≥Grade 3) to polysorbate 80 
containing drugs 
• 
Other concurrent serious illness or medical conditions 
• 
Inadequate organ function as evidenced by the following peripheral blood counts 
and serum biochemistry at enrolment: 
• 
Neutrophils ≤1.5 x 109/L 
• 
Haemoglobin ≤10 g/dL 
• 
Platelets ≤100 x 109/L 
• 
Total bilirubin > 1.5 X upper limit of normal (ULN) 
• 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT)≥1.5 x ULN 
• 
Alanine aminotransferase/serum glutamate pyruvate transaminase 
(ALT/SGPT)≥1.5 x ULN 
• 
Electrocardiogram (ECG) evidence of uncontrolled cardiac arrhythmias, angina 
pectoris, and/or hypertension, history of congestive heart failure, or myocardial 
infarction within last 6 months. 
• 
Uncontrolled diabetes mellitus. 
• 
Active uncontrolled gastro-oesophageal reflux disease (GORD). 
• 
Active infection requiring systemic antibiotic or anti-fungal medication 
• 
Participation in another clinical trial with any investigational drug within 30 days 

 
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prior to study enrolment. 
• 
Concurrent or planned treatment with strong inhibitors of cytochrome P450 
3A4/5. A 1-week washout period is necessary for patients who are already on 
these treatments. 
• 
Concurrent or planned treatment with strong inducers of cytochrome P450 
3A4/5. A 1-week washout period is necessary for patients who are already on 
these treatments. 
• 
Contraindications to cisplatin. 
• 
Patient with reproductive potential not implementing an accepted and effective 
method of contraception. 
• 
Concurrent yellow fever vaccine 
 
 
5 
ENDPOINTS 
 
5.1 
Primary 
 
The primary endpoint is the overall response rate (complete remission rate + partial 
remission rate). 
 
5.2 
Secondary 
 
• Progression free survival 
• Overall survival 
• Acute toxicity (defined by CTCAE v4.03) after each cycle  
• Quality of life during treatment using questionnaire EORTC QLQ C-30 and sup-
porting module BLM-30 
• Quality adjusted life years assessed by EQ-5D 

 
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5.3 
Definition and recording of response and disease progression 
 
Pathologic response is determined by Tumour (T) stage on histopathological ex-
amination of the radical cystectomy specimen and comparison with diagnostic 
pathological findings.  T stage is defined using the American Joint Committee of 
Cancer (AJCC) 2010 staging manual (39): 
 
• 
pTX 
Primary tumour cannot be assessed 
• 
pT0 
No evidence of primary tumour 
• 
pTa 
Noninvasive papillary carcinoma 
• 
pTis Carcinoma in situ 
• 
pT1 
Tumour invades subepithelial connective tissue 
• 
pT2a Tumour invades superficial muscularis propria (inner half) 
 
• 
pT2b Tumour invades deep muscularis propria (outer half) 
• 
pT3a Tumour invades perivesical tissue microscopically 
• 
pT3b Tumour invades perivesical tissue macroscopically (extravesical mass) 
• 
pT4a Tumour invades periprostatic stroma, uterus or vagina 
• 
pT4b Tumour invades pelvic wall or abdominal wall 
 
Response assessment for the purpose of reporting the primary endpoint is 
determined by pathologic staging at cystectomy (partial response, complete 
response, no response or progression of disease) performed by the reporting 
pathologist at the treating centre.  All pathology specimens must be reviewed by a 
multidisciplinary team (MDT) specialising in the treatment of urological 
malignancies.   
 
Radiological progression on cross sectional imaging (CT) is defined as a signifi-
cant increase in the size of pre-existing disease according to RECIST criteria ver-
sion 1.1 (an increase of at least 20% in the longest diameter, see Appendix 1) or the 
development of new metastases.  RECIST criteria are provided in this protocol for 
the purposes of reporting disease progression, where it occurs.  RECIST criteria are 
not used as the primary method of assessing response to chemotherapy for the 
purposes of reporting the primary endpoint (where pathologic response is used). 
 
Recurrence is defined as the development of new metastases in a patient who was 
previously in complete clinical remission. Recurrence may be: 
 
Local: at the primary site 
Regional: from the primary site to the local lymph node basin 
Distant: beyond the locoregional lymph nodes 
 
Details of all recurrences must be included on the case report forms (CRFs). 
 

 
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6  
REGISTRATION 
 
Central registration will be performed by coordinating staff at the Clinical Trials Unit, 
Bristol Haematology and Oncology Centre, on behalf of the sponsor (UH Bristol). 
 
All registered patients must be fit to receive chemotherapy and to undergo radical 
cystectomy.  An eligibility checklist must be completed by the clinician/research 
nurse prior to registration. The following information will be required: 
 
• Name of cancer centre, treating hospital(s), oncology consultant and person ran-
domising patient; 
• 
Confirmation that patient is eligible for the trial by completion of the checklist; 
• 
Confirmation that the disease being followed in the trial has been 
assessed by cystoscopic biopsy or transurethral resection within 2 months and CT  
imaging within 6 weeks of scheduled start date of chemotherapy; 
• 
Confirmation that patient has given written informed consent for registration; 
• 
Patient’s full name, date of birth, hospital number and NHS number.  These will be 
collected to allow tracing through GP records to assist with the collection of long 
term follow-up information. Data will be stored in a log by the Principal Investigator 
and stored in accordance with the arrangements set out in this protocol.    
 
 
The patient will be assigned a unique trial identification number (Trial ID).  This trial 
ID is recorded on all documentation and will be used for identification purposes in 
the Bristol Bladder Trial and both its associated substudies.   
 
Patients should commence chemotherapy within 2 weeks of registration. 
 
7 
TRIAL EVALUATIONS 
 
7.1  
Baseline 
 
Patients will undergo general assessment and assessment of their disease to in-
clude: 
• 
Physical examination (including height, weight and body surface area) to assess fit-
ness and WHO performance status; vital signs (blood pressure, heart rate, respira-
tory rate) 
• 
Recording of concomitant medication use, with relevant dates; 
• 
ECG; 
• 
CT scan of chest, abdomen and pelvis to be performed within 6 weeks of scheduled 
start date of chemotherapy; 
• 
DCE MRI of pelvis to be performed within 4 weeks of scheduled start date of chem-
otherapy if participating in the DCE MRI substudy; 
• 
Peripheral blood test for CTC measurement, if participating in the CTC substudy  
• 
Full blood count, U+E, liver function tests (to include ALP, ALT and/or AST, Bil and 
 
GGT); 
• 
GFR to be assessed according to local practice (recommended technique of eGFR 
using the CKD-EPI formula (see Appendix 2)); 
• 
Baseline assessment of symptoms using common toxicity scoring (CTCAE v4.03). 
• 
Completion of Quality of life questionnaires EORTC QLQ C-30 (with supporting 
module BLM-30) and EQ-5D. 
 
7.2  
On-treatment assessments 

 
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Patients will be seen and assessed within 3 days prior to each cycle of chemother-
apy. Assessment should include: 
 
• 
Physical examination (including height, weight and body surface area) and vital 
signs to include blood pressure, heart rate, respiratory rate; 
• 
BSA (should be calculated as per local practice); 
• 
Full blood count, U+E, liver function tests (to include ALP, ALT and/or AST, Bil and 
 
GGT); 
• 
Full blood count only (without biochemistry) to be checked Day 8 and 15 of cycle 1  
• 
GFR to be assessed according to local practice (recommended technique of eGFR 
using the CKD-EPI formula (see Appendix 2)); 
• 
Safety assessment (CTCAE v4.03); 
• 
Updated recording of concomitant medication use, with relevant dates; 
• 
Quality of life questionnaires EORTC QLQ C-30 (with supporting module BLM-30) 
and EQ-5D. 
• 
CT scan of chest, abdomen and pelvis to be carried out after the third cycle of 
chemotherapy; 
• 
Cystoscopic examination of the bladder to be carried out after the third cycle of 
chemotherapy; 
• 
DCE MRI of pelvis to be performed after the first cycle of chemotherapy, and after 
the third cycle, if participating in the DCE MRI substudy  
• 
Blood test for circulating tumour cell (CTC) measurement prior to each cycle of 
chemotherapy if participating in the CTC substudy  
 
7.3 
End of chemotherapy treatment  
 
Patients should be seen 3-5 weeks after commencement of their final cycle of 
chemotherapy. Assessments should include: 
 
• 
Physical examination to assess fitness and WHO performance status; 
• 
Full blood count, U+E, liver function tests (to include ALP, ALT and/or AST, Bil and 
 
GGT); 
• 
GFR to be assessed according to local practice (recommended technique of eGFR 
using the CKD-EPI formula (see Appendix 2)); 
• 
Safety assessment (CTCAE v4.03). 
• 
Quality of life questionnaires EORTC QLQ C-30 (with supporting module BLM-30) 
and EQ-5D. 
• 
Blood test for circulating tumour cell (CTC) measurements if participating in the 
CTC substudy  
 
7.4 
Radical Cystectomy 
 
Patients should undergo planned radical cystectomy within 6 weeks of 
commencement of the final cycle of chemotherapy.  Confirmation of the plan to 
proceed to surgery should be discussed by the MDT once the relevant imaging and 
clinical information is available.   
 
Following surgery, histopathological tumour stage, as defined above, should be 
recorded by the MDT and in the patient’s trial documentation.   
 
 

 
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7.5 
Long term follow-up 
 
Long-term follow-up is undertaken at the patient’s original treatment/referral centre 
and is in accordance with local guidelines.  Survival data and dates of progression 
events may be recorded remotely via contact with the patient and/or the patient’s 
GP.  Survival data are collected by the trial coordinator and recorded in the individ-
ual patient’s CRF. 
 
 
7.6 
 Qualitative data 
 
Data collection forms for each visit will allow clinicians and/or participants to enter 
free text, to record data considered to be important but not addressed by this proto-
col.  This may aid future design of larger studies. 
 

 
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7.7 Schema of Trial Evaluations (optional substudy evaluations are shaded) 
 
 
 
 
 
 
 
Trial Evaluation 
 
 
 
 
 
Diagnosis 
 
 
Baseline2 
 
Cycle 
1 
Day 8 
 
Cycle  
1 
Day 
15 
 
Pre 
Cycle 2 
 
Pre 
Cycle 3 
 
Pre 
Cycle 4 
 
End of 
Chemo-
therapy7 
Months following radical cystectomy 
Via telephone 
3 
6 
9 
12 
18 
24 
36 
48 
60 
 
 
 
 
 
Within 3 
days of 
treatment 
Within 3 
days of 
treatment 
Within 3 
days of 
treatment 
 
 
 
 
 
 
 
 
 
 
Cystoscopy with diagnostic histology1 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CT chest, abdomen & pelvis 
(Within 6 weeks of treatment) 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, physical examination 
 
X 
 
 
 
X8 
X8 
X8 
X 
 
 
 
 
 
 
 
 
 
Recording concomitant medication 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Body surface area 
 
X 
 
 
 
X8 
X8 
X8 
 
 
 
 
 
 
 
 
 
 
Haematology  
 
X5 
X 
X 
X8 
X8 
X8 
X 
 
 
 
 
 
 
 
 
 
Biochemistry 
 
X5 
 
 
X8 
X8 
X8 
x 
 
 
 
 
 
 
 
 
 
GFR6 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
ECG 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events and safety 
(CTCAE v4.03) 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Quality of Life assessment 
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
MRI pelvis  
 
X3 
 
 
X4 
 
X4 
 
 
 
 
 
 
 
 
 
 
CTC measurement  
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Recording survival and progression 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

 
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1. 
Cystoscopy + biopsy within 2 months prior to commenciing first cycle of chemotherapy 
2. 
Within 4 weeks prior to commencing first cycle of chemotherapy (unless otherwise specified) 
3. 
MRI (optional substudy) baseline scan within 2 weeks of commencing first cycle of chemotherapy  
4. 
MRI (optional substudy) within one week prior to cycles 2+4 
5. 
Bloods to be repeated if baseline sample is not within 7 days of first cycle of treatment 
6. 
GFR to be assessed according to local practice (recommended use of eGFR using the CKD-EPI formula (Appendix 2) 
7. 
3-5 weeks after commencement of the last cycle of chemotherapy 
8. 
Within 3 days prior to treatment 
 

 
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8 TRIAL TREATMENT 
 
The regimen will consist of cabazitaxel 15mg/m2 followed by cisplatin 70mg/m2  day 1 with 
cycle duration of 21 days, 4 cycles to be given in total with formal restaging after 3 cycles. 
 
Day 
Drug 
Dose 
Regimen 
 
1 
Cabazitaxel 15mg/m2 
Intravenous infusion over 1 hour. Premedication is 
required to prevent allergic reaction (see section 8.2) 
1 
 
 
Cisplatin 
70mg/m2 
Intravenous infusion over 1-2 hours preceded by 1 
litre sodium chloride 0.9% (with or without potassium 
and magnesium supplementation, in accordance 
with local policy and practice) over 2 hours and fol-
lowed by sodium chloride 0.9% 1 litre (with or with-
out potassium and magnesium supplementation, in 
accordance with local policy and practice) over 2 
hours. 
 
 
 
Premedication and anti-emetic regimens may be given in accordance with local policy and 
practice.  Suggested recommended premedication and antiemetics are outlined in sections 
8.2 and 8.3.  
 
For further information and information on disallowed concomitant medication please refer 
to the SmPC.  Unless otherwise specified, all diluents/volumes used to give this chemo-
therapy regimen should be according to local practice and the SmPC. 
 
Primary prophylaxis with Granulocyte Colony Stimulating Factor (G-CSF) is manda-
tory for all patients. See section 8.4 below. If contraindication(s) to G-CSF admin-
istration exist, study treatment may only proceed with the approval of the Chief In-
vestigator. 
 
8.1 Drug supplies and labelling 
 
Cisplatin and Cabazitaxel 
 
• 
For supplies of cisplatin normal hospital stock should be used.  
• 
Supplies of cabazitaxel will be provided by sanofi-aventis.  
• 
For cisplatin and cabazitaxel, drug accountability, storage requirements, 
destruction and labelling guidelines are contained within the Clinical Trial Agree-
ment and Trial Guidance Notes.  
• 
All drugs should be labelled ‘for clinical trial use only’. 
• 
For all information on drug stability please refer to each SmPC. 
 

 
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8.2 Pre-Medication 
Cabazitaxel 
The following recommended premedication regimen should be performed at least 30 
minutes prior to each administration of cabazitaxel to mitigate the risk and severity of hy-
persensitivity.   
• Chlorphenamine 10mg IV 
• Dexamethasone 8mg IV (included in antiemetic prophylaxis, see section 8.3. A du-
plicate dose is not required.)   
• Ranitidine 50mg IV 
Antiemetic prophylaxis is recommended and is detailed in section 8.3.  
Cisplatin 
Apart from hydration (section 8.1) and antiemetic prophylaxis (section 8.3) no additional 
premedication is required prior to administration of Cisplatin. 
 
 
8.3 Anti-Emetics 
 
Suggested additional ‘as required’ antiemetics are detailed in the table below for each cy-
cle of chemotherapy but may vary according to local practice.  Where doubt exists the ap-
proval of the Chief Investigator should be sought. 
 
 
Day 
Timing 
Regimen 
 
1 
60 minutes before chemotherapy.   
 
 
Ondansetron 8mg IV/PO 
Aprepitant 125mg PO 
Dexamethasone 8mg IV- duplicate dose 
not required, see above 
 
1 
12 hours after chemotherapy 
Ondansetron 8mg PO 
 
2 and 3 
- 
Aprepitant 80mg PO 
Dexamethasone 4mg BD PO 
Domperidone 10-20mg prn QDS PO 
 
4 
- 
Dexamethasone 4mg BD PO 
Domperidone 10-20mg prn QDS PO 
 
5-21 
- 
Domperidone 10-20mg prn QDS PO 
 
 
 
 
 

 
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8.4 Guidelines for the Management of Toxicity 
 
Reasonable efforts should be taken to minimise dose reduction and treatment delays 
in order to maintain dose-intensity and cumulative dose-delivery. Patients whose 
treatment is delayed because of toxicity should be evaluated on a weekly basis until 
adequate recovery has been made. If there is more than 2 weeks’ delay then patient 
should be withdrawn from the study. 
 
Primary prophylaxis using G-CSF must be used unless contraindications exist. 
The recommended regimen is Pegylated G-CSF 6mg subcutaneously 24 hours 
after administration of chemotherapy. Patients with contraindications to G-CSF 
administration may only proceed with trial treatment with the approval of the 
Chief Investigator.   
 
Safety assessments are recorded according to NCI Common Terminology Criteria for 
Adverse Events v4.03 (NCI CTC AE v4.03,).  For further information on expected tox-
icities refer to SmPCs for individual drugs. 
 
Cisplatin 
 
• Full Blood Count and urea, creatinine, sodium, potassium and magnesium must be 
measured ideally during the 48 hours prior to each cycle (where this is not possible 
this may be extended to 72 hours, but if the results do not meet treatment criteria at 
this point they MUST be repeated within 24 hours prior to each cycle).  
 
• Adequate electrolyte replacement should be incorporated into the pre- and post-
hydration schedule. A sample hydration protocol is detailed in the regimen above 
but this may be modified according to local practice and with the agreement of the 
Chief Investigator. 
 
• GFR (recommended technique of eGFR using the CKD-EPI formula (see Appendix 
2)) should be used to assess continuing adequate renal function prior to each cycle. 
Treatment should only proceed in accordance with GFR guidance given in section 
8.5 (below). 
 
 
Cabazitaxel 
• Hypersensitivity reactions: All patients should be pre-medicated prior to the initia-
tion of the infusion of cabazitaxel (see section 8.2).  
o Hypersensitivity reactions that occur despite premedication are very likely to 
occur within a few minutes of start of the first or of the second infusion of 
cabazitaxel.  Therefore, during the 1st and the 2nd infusions, careful evalua-
tion of general sense of wellbeing and of blood pressure and heart rate will 
be performed for at least the first 10 minutes, so that immediate intervention 
would occur in response to symptoms of an untoward reaction.   
o Facilities and equipment for resuscitation along with the medications (i.e. an-
tihistamine, corticosteroids, aminophylline and epinephrine) must immediate-
ly be available.  If a reaction occurs, the specific treatment that can be medi-
cally indicated for a given symptom (e.g. epinephrine in case of anaphylactic 

 
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shock, aminophylline in case of bronchospasm etc.) will be instituted.  In ad-
dition, it is recommended to take the following measures: 
 
 
Mild: localised cutane-
ous reaction such as 
pruritus, flushing, rash 
• Consider decreasing the rate of infusion un-
til recovery of symptoms, stay at bedside 
• Complete cabazitaxel at the initial planned 
rate 
Moderate: generalised 
pruritus, more severe 
flushing or rash, mild 
dyspnoea, hypotension 
with systolic B.P. 
>80mmHg 
• Stop cabazitaxel infusion 
• Give IV chlorphenamine 10mg and/or hy-
drocortisone 200mg 
• Once all signs and/or symptoms of hyper-
sensitivity reaction disappear, cabazitaxel 
may be reinfused within 24 hours from the 
interruption, if medically appropriate 
• Re-administer premedication regimen as 
described in section 8.2 when cabazitaxel is 
infused more than 3 hours after the interrup-
tion 
• Administer cabazitaxel over 2 hours for all 
subsequent infusions 
Severe: bronchospasm, 
generalised urticaria, 
hypotension with systol-
ic B.P.  ≤80mmHg, an-
gioedema 
• Stop cabazitaxel infusion 
• Give IV chlorphenamine 10mg and/or hy-
drocortisone 200mg  
• Add epinephrine or bronchodilators and/or 
IV plasma expanders if indicated 
• Once all signs and/or symptoms of hyper-
sensitivity reaction disappear, cabazitaxel 
may be reinfused within 24 hours from the 
interruption, if medically appropriate 
• Re-administer premedication as described 
in section 8.2 when cabazitaxel is infused 
more than 3 hours after the  interruption 
• Administer cabazitaxel over 2 hours for all 
subsequent infusions  
o Patients experiencing a hypersensitivity reaction ≥ Grade 3 ( CTCAE v.4.03) 
must stop treatment with cabazitaxel and will be withdrawn from the study.   

 
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8.5 Dose Modifications and Delays 
 
This section outlines recommended dose modifications for common potential toxicities.  It 
is not exhaustive.  Where doubt exists regarding dose modifications and delays, individual 
patients should be discussed with the Chief Investigator. 
In general, any patient requiring greater than 2 weeks’ delay for recovery of toxicity 
should be withdrawn from the study. Any further chemotherapy is then given at the 
discretion of the treating clinician and is beyond the scope of this protocol. 
 
Haematologic Toxicity 
 
• No new cycle of chemotherapy should commence unless WBC≥ 3.0 x 109/L, ANC≥ 
1.5 x 109/L and Platelet count ≥  75 x 109/L.  The use of G-CSF is mandatory as 
primary prophylaxis (see section 8.4). 
 
• A 20% dose reduction in both drugs is recommended for subsequent cycles if one 
or more of the following occurs:  
 
o Grade IV neutropenia (ANC <0.5 x109/L) with fever ≥ 38.5ºC;  
o Infection with ANC <1.0 x 109/L; 
o Thrombocytopenia with platelets <10 x109/L for more than 3 days; or  
o Thrombocytopenia with active bleeding.  
 
• If afebrile grade IV neutropenia (ANC <0.5 x109/L) is seen on day 8 or 15, prophy-
lactic oral ciprofloxacin 500 mg b.d. x 7days should be used in subsequent cycles. 
 
• Patients with anaemia should be considered for blood transfusion if clinically indi-
cated.  Chemotherapy should be delayed until recovery or correction if haemoglobin 
is <9.0 g/dl.   
 
Neurotoxicity 
 
• Patients with grade ≥2 peripheral neuropathy should discontinue chemotherapy until 
recovery of symptoms to ≤grade 1.  Subsequent doses of both cisplatin and caba-
zitaxel should then be reduced by 20%.  If further grade ≥2 peripheral neuropathy 
occurs, the patient should be withdrawn from the study.  Any further chemotherapy 
is then given at the discretion of the treating clinician. 
 
• Chemotherapy should be stopped and the patient withdrawn from the study if grade 
3 or 4 neurotoxicity occurs.  Any further chemotherapy is then given at the discre-
tion of the treating clinician. 
 
 Nephrotoxicity 
 
Grade 3 or 4 hypomagnesaemia should be treated accordingly and reported as an 
SAE 
 
 
• In the event of renal toxicity during study treatment, dose reductions for cisplatin 
and cabazitaxel should be according to the table and notes below.  Patients with 

 
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eGFR < 50ml/min should undergo formal GFR testing with 51Cr- EDTA before pro-
ceeding with the next cycle of chemotherapy.  For other patients, GFR may be as-
sessed according to local practice. Recommended technique using the CKD-EPI 
formula (Appendix 2).   
 
 
• Patients developing acute renal impairment with eGFR <50ml/min after commenc-
ing study chemotherapy should be appropriately treated and monitored carefully. 
Study chemotherapy may be recommenced once eGFR has recovered to 
≥50m/min.  Cabazitaxel is minimally excreted through the kidney.  Limited data are 
available for patients with moderate or severe renal impairment.   
 
Gastrointestinal Toxicity 
 
• Patients with grade ≥3 diarrhoea, persisting despite appropriate treatment, including 
loperamide and fluid and electrolyte replacement, should discontinue chemotherapy 
until symptoms have resolved to ≤grade 1.  Subsequent doses of cabazitaxel 
should then be reduced by 20% and a cisplatin dose reduction should be consid-
ered.   
• If further grade ≥3 diarrhoea occurs, the patient should be withdrawn from the study.  
Any further chemotherapy is then given at the discretion of the treating clinician. 
 
Hepatic Impairment 
Cabazitaxel is contraindicated in patients with Hepatic impairment (bilirubin >1.5 x 
ULN, or AST and/or ALT 1.5 × ULN).  If this occurs chemotherapy should be with-
held and liver function tests checked weekly until recovery to bilirubun ≤1xULN AND 
AST and/or ALT <1.5 x ULN.  Where this persists, resulting in greater than 2 weeks’ 
delay, study chemotherapy treatment should be discontinued and the patient with-
drawn from the study. 
 
 
 
 
Recovery of chemotherapy related toxicities 
 
Following recovery of toxicity which has required dose reduction, it is permissible, 
but not mandatory, for patients to receive chemotherapy at the 100% dose for 
subsequent cycles provided all assessments are within the limits set out above.   
 
    
 Concomitant Medications 
 
During the study, the Investigators may prescribe any concomitant medications as 
deemed necessary.  Supportive treatment as medically indicated for the patient’s 
well-being (including hyperalimentation, blood transfusion, treatment for pain relief) 
may be prescribed at the investigator’s discretion.   
eGFR 
Cisplatin dose 
Cabazitaxel dose 
≥60 mls/min 
100% 
100% 
50- <60mls/min 
75% 
100% 
<50 mls/min 
Check formal GFR, 
Delay until recovery 
Check formal GFR, 
Delay until recovery 

 
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During treatment with cabazitaxel, the use of potent inhibitors or potent inducers of 
cytochrome P450 3A4/5 should be avoided.  See appendix 5. 
 
 
8.7 
Contraception 
 
Patients with reproductive potential should be advised to adhere to accepted and ef-
fective method(s) of birth control during treatment with chemotherapy and for at 
least 1 year after last administration.   
 
 
9 SAFETY & PHARMACOVIGILANCE 
 
9.1  
Definitions 
 
9.1.1 Adverse Events (AEs) 
 
An adverse event is any untoward medical occurrence in a patient administered a drug; the 
event does not necessarily have a causal relationship with the treatment or usage. 
 
9.1.2 Serious Adverse Events (SAEs)  
 
An SAE is any untoward medical occurrence or reaction that occurs after the commence-
ment of treatment and within 30 days of the last administration of the trial regimen, that at 
any dose: 
 
• 
Results in death; 
 
• 
Is life threatening, (Note: the term “life-threatening refers to an event/reaction in which 
the patient was at risk of death at the time of the event/reaction; it does not refer to an 
event/ reaction which hypothetically might have caused death if it were more severe), 
 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; 
 
• 
Is a congenital anomaly/birth defect; or 
 
• 
Is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious, such as 
important medical events that might not be immediately life-threatening or result in 
death or hospitalization, but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed in the definition above. 
 
• 
Grade 3 or 4 hypomagnesaemia should be treated accordingly and report-
ed as an SAE 
• 
 
 
• 
Related SAE: there is a reasonable possibility according to the investigator and/or the 
sponsor that the Product may have caused the event. 
 
• 
Unexpected: An adverse drug reaction (ADR) whose nature, severity, specificity, or out-
come is not consistent with the term or description used in the reference document 
(e.g., Package Insert) should be considered unexpected.  An expected ADR with a fatal 
outcome should be considered unexpected unless the local/regional product labelling 
specifically states that the ADR might be associated with a fatal outcome. 

 
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9.1.3 Serious Adverse Reactions (SAR) 
 
A SAR is an SAE that has a definite, probable or possible causal relationship to the trial drug. 
 
9.1.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
Any adverse reactions that have a suspected relationship to the trial drug that are both seri-
ous and unexpected, as judged by the CI. 
 
An unexpected serious adverse reaction is one that is not listed as a known toxicity of the 
investigational drug in the current Summary of Product Characteristics (SmPC)  dated 
20/04/2017 section 4.8. 
 
9.1.5 Pregnancy  
 
 
Pregnancy occurring in a patient or a partner of a patient included in this trial will be recorded 
as an AE in all cases.  It will be qualified as an SAE only if it fulfils the SAE criteria.  In the 
event of pregnancy, the Clinical Trials Unit  should be informed immediately (within 1 working 
day) via email to bristolbladder@uhbristol.nhs.uk, even if the event does not fulfil a serious-
ness criterion, using the AE form.  Follow-up of the pregnancy is mandatory until the out-
come has been determined.  
 
9.1.6 Overdose 
 
Overdose of IMP occurring in a patient defined as ‘the administration of a quantity of a me-
dicinal product given per administration or cumulatively, which is above the maximum rec-
ommended dose according to the authorised product information. Clinical judgement should 
always be applied.’ will be recorded as an AE in all cases. It will be qualified as an SAE only 
if it fulfils the SAE criteria.  In the event of overdose, the Clinical Trials Unit should be in-
formed immediately (within 1 working day) via email to bristolbladder@uhbristol.nhs.uk, even 
if the event does not fulfil a seriousness criterion, using the AE form.   
 
9.2  
Causality (relatedness) 
The assignment of causality for serious adverse events should be made by the investigator 
responsible for the care of the patient using the definitions in Table 1 (below). If any doubt 
about the causality the investigator should inform the sponsor who will notify the Chief Inves-
tigator. Pharmaceutical companies and/or other clinicians may be asked to advise. 
 
Table 1 – Definitions for causality 
 
Relationship 
Description 
 
Unrelated 
There is no evidence of any causal relationship with the trial drug 
 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the 
event did not occur within a reasonable time after administration of the 
trial medication). There is another reasonable explanation for the event 
(e.g. the patient’s clinical condition, other concomitant treatment) 
 
Possible 
There is some evidence to suggest a causal relationship (e.g. because the 
event occurs within a reasonable time after administration of the trial medica-
tion). However, the influence of other factors may have contributed to the 
event (e.g. the patient’s clinical condition, other concomitant treatments) 
 
Probable 
There is evidence to suggest a causal relationship, and the influence of other 

 
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factors is unlikely 
Definitely 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
 
Not assessable 
There is insufficient or incomplete evidence to make a clinical judgement of 
the causal relationship 
 
 
 
9.3 Procedure for collecting Adverse Events 
 
For the purpose of this trial, any detrimental change in the patient’s condition that occurs after reg-
istration and within 30 days of the last administration of chemotherapy treatment, which is not due 
to progression of disease (transitional cell carcinoma of the urinary bladder), should be considered 
an AE. 
 
Whenever one or more signs and/or symptoms correspond to a disease or a well-defined syn-
drome only the main disease/syndrome should be reported. The severity of adverse events will be 
graded according to the NCI-CTC criteria  CTCAE Version 4.03.For each sign/symptoms, the 
highest grade observed since the last visit should be reported. 
 
All adverse events (AE) must be reported on the Case Report Forms (CRF). 
 
9.4 Procedure for recording Serious Adverse Events 
 
SAEs in this study that are fatal or life threatening or result in persistent or significant disabil-
ity/incapacity should be reported using a Serious Adverse Event (SAE) form.  
 
Medical and scientific judgement should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life threatening 
or result in death or result in persistent or significant disability/incapacity. 
 
9.5 Reporting of Serious Adverse Events to the Sponsor 
 
Serious adverse events require immediate reporting by fax or email to the sponsor within 24 
hours of the Principal Investigator or designated representative becoming aware of the event. 
Please fax SAE forms for the attention of the sponsor at Research and Innovation, University 
Hospitals Bristol NHS Foundation Trust, Level 3 Education Centre, Upper Maudlin Street, Bristol 
BS2 8AE; Fax: 0117 342 0239.or via e-mail to research@UHBristol.nhs.uk 
Forms must be completed, signed and dated by the site Principal Investigator or designated repre-
sentative.   
 
9.6 Review of Serious Adverse Events 
 
Events reported using an SAE/SAR form will be forwarded to the Chief Investigator immediately (or 
designated representative) for assessment of causality and expectedness. 
 
Centres should respond as soon as possible to requests from the CI or designated representative 
(via the sponsor) for further information that may be required for final assessment. 
 
9.7 Expedited Reporting of SUSARs 
 
If an SAE is defined as a SUSAR (both related and unexpected and is fatal or life threatening, 

 
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The sponsor will report this to the MHRA and the Main REC within 7 days from the date of being 
notified of the event. 
 
If an SAE is defined as a SUSAR and is not fatal or life threatening, the sponsor will report this to 
the MHRA and Main REC within 15 days. 
 
The Principal Investigator at all actively recruiting centres will be informed of any SUSARs occur-
ring within the trial. 
 
9.8 Follow-up of Serious Adverse Events 
 
The patient must be followed-up until clinical recovery is complete and laboratory results have re-
turned to normal, or until disease has stabilised. Information on final diagnosis and outcome of 
SAE which may not be available at the time the SAE was initially reported should be completed on 
the follow-up SAE form and faxed or emailed to the sponsor within 24 hours of site becoming 
aware of this information.  
 
9.9 Annual Reporting of Serious Adverse Events 
 
An annual report will be provided to the MHRA and the Main REC by the sponsor at the end of the 
reporting year.  This will be defined as the anniversary of the date when the Clinical Trials Authori-
sation (CTA) was obtained. This will include all SARs and SUSARs. 

 
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10  FURTHER MANAGEMENT AT THE END OF STUDY TREATMENT 
 
Further medical or surgical treatment following radical cystectomy is at the 
discretion of the treating clinician in consultation with the patient.  Details of such 
management are beyond the scope of this protocol.   
 
If further treatment for transitional cell carcinoma of the urinary bladder is required 
during the study period, then details of such treatment should be recorded in the 
CRF. 
 
11 
STATISTICAL CONSIDERATIONS 
 
11.1 Choice of principal endpoints 
 
To determine the activity of cabazitaxel and cisplatin in invasive bladder cancer 
(transitional cell carcinoma) patients, the principal endpoint for the study will be the 
overall response rate (complete remission + partial remission) determined by patho-
logic staging at radical cystectomy (see above). 
 
11.2 Sample size calculations 
 
• It is assumed that a response rate of less than 35% is not sufficiently large enough 
to warrant further investigation in an expanded phase II or phase III setting, but that 
a rate of 60% or higher would warrant further investigation. 
 
• Using an exact test for a single proportion, p0=0.35 and p1=0.60, setting al-
pha=0.05 (onesided) and power = 80%, 26 patients are required.  
 
• In order to recruit 26 patients evaluable for the primary endpoint, recruitment will be 
extended to replace patients deemed not evaluable. It is anticipated that a total of 
approximately 30 patients will need to be recruited (see section 18.1). 
 
• Recruitment is until end of December 2017.  
 
11.3 Stopping rules 
 
The study will be stopped at the point at which there is a 99% chance that the 
response rate is less than 60%.  If no patients are seen to respond to treatment, the 
study will stop at the point at which 9 patients results are known.  A formal 
assessment of the 99% one sided lower confidence limit will be calculated using the 
exact binomial method when requested by the trial management group in response 
to lower than expected levels of response and the stopping rule initiated 
accordingly.  Thus in the event that no responses are seen in the first 9 patients, an 
Independent Data Monitoring Committee (IDMC) would be convened. 
 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
24 
 
11.4 Analysis methods 
 
11.4.1 Primary endpoint 
 
Response will be evaluated according to pathologic T staging at radical cystectomy 
 using the AJCC TNM system (39). The objective response rate for this study is de-
fined as the proportion of patients having achieved partial or complete remission 
 according to their pathologic stage at cystectomy compared with pathologic T stage 
at diagnosis. For the purposes of the trial, pathology must be viewed by a multidis-
ciplinary team (MDT) specialising in the management of urological malignancies.   
 
Analysis will include tabulation of baseline characteristics of recruited patients.  
Intention to treat analysis will be used.  Baseline characteristics for those patients 
not completing trial treatment will be tabulated for comparison with treated patients, 
to ensure generalisability of results.  Baseline characteristics will include (but are 
not limited to) demographic data, tumour stage and grade.   
 
11.4.2Secondary endpoints 
 
• Progression-free survival 
o Progression free survival will be calculated from the date of study entry until a 
progression occurs.  Progression events are defined as clinical, pathologic or 
radiologically documented disease progression, or death from any cause, Pa-
tients free from a progression event will be censored on the date of last follow 
up. 
o A progression-free survival curve will be generated using the methods of Kaplan 
and Meier. All patients registered in the study will be included. Median PFS rate 
will be reported with 95% CIs. 
o Duration of response as measured by Kaplan-Meier at each follow-up, or until 
progression, will be reported. 
 
• Overall survival 
o An overall survival curve will be generated using the methods of Kaplan and 
Meier. All patients registered in the study will be included. The median overall 
survival will be reported with 95% CI. 
 
• Toxicity 
o The proportion of patients experiencing grade 3 or 4 toxicity as measured by 
NCI-CTCAE v4.03 at trial visits or until progression and the number of SAEs will 
be reported. 
 
• Quality of Life 
o Quality of Life is assessed using questionnaires EORTC QLQ C-30 (with sup-
porting module BLM-30) and EQ-5D at each trial visit.  Quality of life data will be 
reported for each time point and in terms of quality-adjusted life years (QALYs) 
using EQ-5D.   
o A repeated measure analysis of variance will be used to assess quality of life 
changes during the course of the study. 
 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
25 
 
 
• Qualitative data 
o Data collection forms for each visit will allow clinicians and/or participants to en-
ter free text, to record data considered to be important but not addressed by this 
protocol.  This may aid future design of larger studies. 
 
11.4.3 Missing Data 
 
In the event that data for an individual patient has not been collected, after the 
response assessment has taken place but in the absence of an event, a Last-
Observation-Carried-Forward analysis will be performed. 
 
 
11.5 Frequency of analyses 
 
The Trial Management Group will meet regularly to examine safety and efficacy.  An 
interim analysis will be required after the first 9 patients have undergone radical cys-
tectomy.  An Independent Data Monitoring Committee will be asked to advise on 
continuing recruitment should the response rate be lower than anticipated (see sec-
tion 11.3). 
 
12 
RESEARCH GOVERNANCE 
 
12.1  Trial Administration 
 
The sponsor for this trial is University Hospitals Bristol NHS Foundation Trust 
(referred to in this protocol as UH Bristol) 
 
Sponsorship activities and delegated responsibilities are in accordance with The 
Medicines for Human Use (Clinical Trials) Regulations 2004 as amended and in line 
with the Research Governance Framework for Health and Social Care and the prin-
ciples of Good Clinical Practice.  
 
All parties agree to allow inspection of their premises by the competent authorities.  
 
 
 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
26 
 
 
12.1.1 Responsibilities 
 
UH Bristol has sponsorship responsibility for obtaining authorisation and appropriate 
research ethics committee (REC) opinion (Part 3 of the Regulations) and for phar-
macovigilance (Part 5 of the Regulations).  
 
The sponsor warrants that the Study will be performed in compliance with all appli-
cable local and international laws and regulations, including without limitation ICH 
E6 guidelines for Good Clinical Practices.  
The sponsor shall be responsible for the respect of all obligations required by appli-
cable local and international laws and regulations.  
The sponsor shall be responsible for all required periodic updates to the health au-
thorities and expedited reporting of all Serious Adverse Events occurring during the 
performance of the study, in accordance with local and regional regulations.  
The sponsor shall also be responsible to provide to the investigators and the Ethics 
Committee all relevant study related information (including information submitted to 
the Health Authorities and any “Dear Investigator Letter” received from Sanofi.  
The sponsor must report the following information in English to the Sanofi Pharma-
covigilance contact: 
• 
Copy of all serious adverse events (SAEs) received from site. 
• 
Copy of all individual Suspected (drug related) and Unexpected Serious Ad-
verse Reactions (SUSARs) at time of submission to Health Authorities (format 
sent to Authorities) or, if submission of SUSAR is not required in the participat-
ing country, such individual reports shall be sent to Sanofi on an ongoing basis. 
• 
In addition to SUSARs, any other events that have been submitted to the Health 
Authorities according to local regulatory requirements in the participating country 
shall be sent to Sanofi at time of submission to these Authorities.  
• 
Any significant safety issues, events or results, e.g., Data Safety Monitoring 
Board recommendations, occurring or found during the course of the Study 
which might affect performance thereof shall be sent to Sanofi on an ongoing 
basis.  
The reference safety text to be used for evaluation of expectedness of adverse 
events will be the current Summary of Product Characteristics (SmPC) dated 
20/04/2017 section 4.8..  
Responsibilities may be delegated to the Chief Investigator (or named Deputy in his 
absence) and to the Clinical Trials Unit, Bristol Haematology and Oncology Centre,   
as deemed appropriate by the sponsor. 
 
 
The delegation of responsibilities does not impact on or alter standard NHS indem-
nity cover.  The agreement of delegated responsibilities is viewed as a partnership 
and as such it is necessary to share pertinent information between the Clinical Tri-
als Unit, Bristol Haematology and Oncology Centre, UH Bristol and the Chief Inves-
tigator, including proposed inspections by the MHRA and/or other regulatory bodies.  
  

 
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27 
 
This is an NHS-sponsored research study. For NHS sponsored research HSG 
(96)48 reference no. 2 refers. If there is negligent harm during the clinical trial when 
the NHS body owes a duty of care to the person harmed, NHS Indemnity covers 
NHS staff, medical academic staff with honorary contracts, and those conducting 
the trial.  
 
NHS Indemnity does not offer no-fault compensation and is unable to agree in ad-
vance to pay compensation for non-negligent harm.  
 
Ex-gratia payments may be considered in the case of a claim. 
 
12.2  Protocol Compliance & Initiation 
 
The Bristol Bladder Trial will be conducted in accordance with the professional and 
regulatory standards required for non-commercial research in the NHS under the 
EU Directive.   
 
12.3  Data Acquisition & On-Site Monitoring 
 
The Bristol Bladder Trial will be monitored and audited in accordance with UH Bris-
tol’s policy. All trial related documents will be made available on request for monitor-
ing and audit by UH Bristol, the relevant Research Ethics Committee and for inspec-
tion by the Medicines and Healthcare products Regulatory Authority or other licens-
ing bodies. 
 
 
12.4  Archiving 
 
Essential documents are documents that individually and collectively permit evalua-
tion of the conduct of the trial and substantiate the quality of the trial data collected. 
Essential documents will be maintained by the Clinical Trials Unit, Bristol Haematol-
ogy and Oncology Centre and at participating centres in a way that will facilitate the 
management of the trial and inspection. Documents will be securely stored and ac-
cess restricted to authorised personnel. Trial documents (paper and electronic) will 
be retained in a secure location during and after the trial has finished. All source 
documents will be retained for a period of 15 years following the end of the study. 
Where trial related information is documented in the medical records – those rec-
ords will be identified by a ‘Do not destroy before dd/mm/yyyy’ label where date is 
15 years after the last patient last visit. 
. 
 
12.5  Data Protection Act  
 
UH Bristol will comply with all aspects of the Data Protection Act 1998. Any re-
quests from patients for access to data held about them should be directed to the 
Trial Coordinator in the first instance, who will refer the request to the Data Protec-
tion Officer. 
 
 

 
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28 
 
 
13  
TRIAL MANAGEMENT 
 
13.1  Trial Management Group 
 
A Trial Management Group (TMG) will be set up and will include the Chief Investi-
gator and identified collaborators, the trial statistician and trial co-ordinator.  Princi-
pal Investigator(s) and key study personnel will be invited to join the TMG as appro-
priate to ensure representation from relevant professionals.   
 
Notwithstanding the legal obligations of the Sponsor and Chief Investigator, the 
TMG will have operational responsibility for the conduct of the trial.  
 
   
 
13.2  Data Monitoring Committee 
 
An Independent Data Monitoring Committee (IDMC) will be established to oversee 
the final safety data and end point analysis of the trial. This committee will be consti-
tuted according to Good Clinical Practice. The IDMC will meet after recruitment has 
concluded and all patients have got to the primary end point. Following this meeting, 
the IDMC will report their findings and recommendations to the TMG. 
 
 
14  
END OF STUDY 
 
For the purposes of Clinical Trial Authorisation (CTA) under the European Union Di-
rective 2001/20/EC, the study is deemed to have ended 5 years after the last pa-
tient has undergone radical cystectomy. 
 
As described above, if no chemotherapy responses are observed in the first 9 eval-
uable patients, stopping rules will apply and an Independent Data Monitoring Com-
mittee (IDMC) would be convened to advise on continued recruitment.   
 
 
 
 
 
 
 
 
 
 
 
 
 
15  
PUBLISHING POLICY 
 
The main trial results will be published in the name of the trial in a peer-reviewed 
journal, on behalf of all collaborators. The manuscript will be prepared by a writing 
group, appointed from amongst the Trial Management Group. All participating cen-

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
29 
 
tres and clinicians will be acknowledged in this publication. All presentations and 
publications relating to the trial must be reviewed and approved by the Trial Man-
agement Group on whose behalf publications should usually be made. Authorship 
of any secondary publications, e.g. relating to the DCE MRI and CTC substudies, 
will reflect the intellectual and time input into these studies, and will not be the same 
as on the primary publication. No investigator may present or attempt to publish da-
ta relating to the trial without prior permission from the Trial Management Group. 
 
The Sponsor, Sanofi and the investigators are committed to the publication and 
widespread dissemination of the results of this study.  This study represents a joint 
effort between Sanofi and the investigators, and as such, the parties agree that the 
recommendation of any party concerning manuscripts or texts shall be taken into 
consideration in the preparation of final scientific documents for publication or 
presentation.  All proposed publications and presentations by the investigators or 
their personnel and associates resulting from or relating to this study must be 
submitted to Sanofi for review and approval 30 days before submission for 
publication or presentation. 
 
If the proposed publication or presentation contains patentable subject matter 
which, at Sanofi’s discretion, warrants intellectual property protection, Sanofi may 
delay any publication or presentation for up to 60 days for review and approval i.e. 
90 days in total. 
 
It is anticipated that the results of this trial and those of the MRI and CTC substud-
ies will contribute to an MD thesis for Dr Susan Masson, Consultant Clinical Oncol-
ogist, University Hospitals Bristol NHS Foundation Trust.   
 
16  
CONFIDENTIALITY AND LIABILITY 
 
16.1  Risk assessment 
 
Generic risk assessment hazards to patients, study and organisation have been 
performed for the trial. 
 
16.2  Liability/Indemnity/Insurance 
 
Indemnity for participating hospitals is provided by the usual NHS indemnity ar-
rangements. 
 
16.3  Patient Confidentiality 
 
The personal data recorded on all documents will be regarded as confidential, and 
any information which would allow individual patients to be identified will not be re-
leased into the public domain.  However, a log of patients’ trial ID numbers, names, 
addresses and hospital numbers kept by the Principal Investigator will be collected 
to allow tracing through GP and national records to assist with the collection of long 
term follow-up information. The investigators must maintain trial documents, which 
are to be held at the participating centre (e.g. patients' written consent forms), in 
strict confidence.  
 
The Principal Investigator must ensure the patients’ confidentiality is maintained. 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
30 
 
The sponsors will maintain the confidentiality of all patient data and will not repro-
duce or disclose any information by which patients could be identified. Representa-
tives of the sponsor and the regulatory authorities are required to have access to 
patient notes for quality assurance purposes. Patient confidentiality will be respect-
ed at all times. In the case of special problems and/or government queries, it is also 
necessary to have access to the complete study records, provided that patient con-
fidentiality is protected. 
 
17  
ETHICAL CONSIDERATIONS 
 
The Bristol Bladder Trial will be performed subject to Research Ethics Committee 
(REC) approval, including any provisions of Site Specific Assessment and local Re-
search and Development (R&D) approval. 
 
Patients should be asked to sign the main consent form after having received both 
verbal and written information. The consent form must be countersigned by the 
Principal Investigator or a designated individual. A record of who the designated in-
dividuals are and the circumstances under which they may countersign consent 
forms must be clearly documented at the research site as part of the Delegation 
Responsibilities Log. This log, together with original copies of all signed patient con-
sent forms, must be available for inspection. 
 
The patient information sheet should be provided in addition to any standard patient 
information sheets that are provided by the centre and which are used in routine 
practice.  
 
 
18 
WITHDRAWAL OF PATIENTS 
 
18.1  Withdrawal of patients from trial treatment 
 
Patients who do not receive their full 4 cycles of cisplatin and cabazitaxel chemo-
therapy for any reason (see below) should be treated with further chemotherapy if 
appropriate, according to local practice, at the discretion of their clinician. Specific 
regimens are beyond the scope of this protocol.  Unless the patient requests other-
wise, all CRFs, including long term follow-up, should be completed, regardless of 
how much treatment is actually received, as an analysis of outcome efficacy data 
will be performed on the basis of intention to treat (i.e. all registered patients). A trial 
deviation form should be completed to record details of deviation from trial treat-
ment. 
 
The following are possible reasons as to why a patient may not receive 4 cycles of 
cisplatin and cabazitaxel chemotherapy: 
 
• 
Unacceptable toxicity 
• 
Adverse event requiring discontinuation of treatment; 
• 
Unforeseen events: any event, which in the judgement of the Investigator makes 
further treatment inadvisable; 
• 
Evidence of disease progression; 
• 
Withdrawal of consent; 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
31 
 
• 
Serious violation of the study protocol (including persistent patient attendance 
failure and persistent non-compliance). 
 
In the principal analysis, where a patient is not evaluable, additional patients will be 
recruited to replace them. A patient is considered not evaluable if: 
 
• 
The patient has not completed any cycles of study cisplatin and cabazitaxel 
chemotherapy for one of the following reasons: 
o Death from any cause 
o  
o Withdrawal from trial for a reason unrelated to drug or disease (e.g. patient 
preference, administrative reasons), regardless of the number of cycles of 
chemotherapy. 
Or 
 
• 
Disease cannot be measured at the end of study treatment for one of the follow-
ing reasons: 
o Death from causes other than bladder cancer 
o Withdrawal from trial for a reason unrelated to drug or disease (e.g. pa-
tient preference, administrative reasons), regardless of the number of cy-
cles of chemotherapy 
 
 
Every attempt should be made to obtain disease assessments for all patients. The 
 
TMG will centrally review all patients to determine if any are non-evaluable and 
 
need to be replaced. 
 
18.2  Withdrawal of patients from trial follow-up 
 
Patients are asked prior to registration to consent to follow-up should they withdraw 
from their allocated treatment (see patient information sheet and consent form), and 
any patient unwilling to give that assurance prior to trial entry should not be regis-
tered. Patients are however free to reverse that decision at any time without giving a 
reason (see below). 
 
A trial deviation form should be completed in the unlikely event that the patient with-
draws consent for further follow-up data to be collected. If this situation is suspect-
ed, clarification should be sought to ensure that the patient is not simply withdraw-
ing from allocated treatment (as above). In the extremely unlikely event that the pa-
tient wishes to have their data removed from the trial completely (the implications of 
this should be discussed with the patient to ensure that this is their intent) this 
should be indicated as such on the trial deviation form. 
 
 

 
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32 
 
 
19 
FINANCIAL MATTERS 
 
 
This trial is investigator designed and led. This trial is supported by a grant from 
Sanofi. 
 
Patients will not be remunerated for participation in this trial.  However due to the 
requirement for additional appointments above those which comprise routine care, 
patients participating in the DCE-MRI substudy may have reasonable travel 
expenses reimbursed for DCE-MRI appointments.   
 
20 
ASSOCIATED STUDIES 
 
20.1 DCE MRI Substudy 
 
This is a concomitant optional substudy evaluating the use of dynamic contrast 
enhanced magnetic resonance imaging during neoadjuvant chemotherapy for 
muscle invasive transitional cell carcinoma of the urinary bladder, as a method of 
early response assessment.   
 
The details of this study are outlined in the protocol. Patients participating in this trial 
who are eligible and willing may enter the study, which will involve additional 
imaging with gadolinium enhanced MRI scanning of the pelvis prior to 
chemotherapy and after one and three cycles of chemotherapy (a total of 3 DCE 
MRI scans).   
 
20.2 CTC Substudy 
 
 
This is a pilot study recording circulating tumour cell (CTC) concentrations prior to 
each cycle of chemotherapy and prior to radical cystectomy.   
 
The details of this study are outlined in the protocol..  Eligible patients participating 
in this trial may enter the study, which will involve taking additional peripheral blood 
samples at the time of collection of ‘routine’ blood samples, with one additional 
sample taken at the end of treatment appointment.   
 
Queries regarding these two substudies should be directed in the first instance to: 
 
Dr Amit Bahl 
 
Consultant Clinical Oncologist 
 
Bristol Haematology + Oncology Centre 
 
Bristol BS2 8ED 
 
Tel 0117 342 3029 
 
 
Dr Susan Masson 
 
Consultant clinical oncologist 
 
Bristol Haematology and Oncology Centre 
 
Horfield Road 
 
Bristol BS2 8ED                                                                                                                              
 
 
 
Tel 0117 342 2418 (secretary) or via mobile pager (limited hours) – please contact 
 
BRI switchboard 0117 923 0000 susan.masson@nhs.net 

 
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REFERENCES 
 
1. Office for National Statistics. Cancer Statistics registrations: registrations of cancer 
diagnosed in 2007, England. 2010. 
2. Welsh Cancer Intelligence and Surveillance Unit. Cancer Incidence in Wales, 2005-
2009. 2011. 
3. ISD Online. Cancer Incidence, Mortality and Survival Data. 2011. 
4. Northern Ireland Cancer Registry. Cancer Incidence and Mortality. 2010. 
5. Calabrò F, Sternberg CN.  Neoadjuvant and adjuvant chemotherapy in muscle-invasive 
bladder cancer. European Urology Feb 2009 55(2):348-58. 
6. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant Chemotherapy in 
Invasive Bladder Cancer: A Systematic Review and Meta-analysis. Lancet 2003 Jun 
361(9373):1927-34. 
7. Advanced Bladder Cancer Meta-analysis Collaboration.Neoadjuvant chemotherapy in 
invasive bladder cancer: update of a systematic review and meta-analysis of individual 
patient data.  European Urology 2005 Aug 48(2):202-205, discussion 205-206. 
8. Winquist E, Kirchner TS, Segal R et al.  Neoadjuvant chemotherapy for transitional cell 
carcinoma of the bladder: a systematic review and meta-analysis.  Journal of Urology 2004 
Feb 171(2 part 1):561-569. 
9. Grossman HB, Natale RB, Tangen CM.  Neoadjuvant chemotherapy plus cystectomy 
compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003  
Aug 349(9):859-866. 
10. Muñoz A, Barceló JR, López-Vivanco G.  Chemotherapy for bladder cancer.  N Engl J 
Med 2003 Dec 349(23):2272-3; author reply 2272-3. 
11. Sonpavde G, Rawat A, Naveed F.  Chemotherapy for bladder cancer.  N Engl J Med 
2003 Dec Vol. 349(23):2272-3; author reply 2272-3. 
12. Dash A, Pettus JA 4th, Herr HW. A role for neoadjuvant gemcitabine plus cisplatin in 
muscle-invasive urothelial carcinoma of the bladder: a retrospective experience.  Cancer 
2008 Nov 113(9): 2471-7. 
13. von der Maase H, Hansen SW, Roberts JT et al.Gemcitabine and cisplatin versus 
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder 
cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin 
Oncol 2000 Sep 18(17):3068-77. 
14. von der Maase H, Sengelov L, Roberts JT et al. Long-term survival results of a 
randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, 
doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005 Jul 
23(21):4602-8. 
15. Otto T, Bex A, Krege S et al. Paclitaxel-based second-line therapy for patients with 
advanced chemotherapy-resistant bladder carcinoma (M1): a clinical Phase II study.  
Cancer 1997 Aug 80(3):465-70. 
16. Di Lorenzo G, Montesarchio V, Autorino R, et al.Phase 1/2 Study of Intravenous 
Paclitaxel and Oral Cyclophosphamide in Pretreated Metastatic Urothelial Bladder Cancer 
Patients. Cancer 2009 115:517-23. 
17. Tsavaris N, Kosmas C, Skopelitis H, et al.Methotrexate-Paclitaxel-Epirubicin-
Carboplatin (M-TEC) Combination Chemotherapy in Patients with Advanced Bladder 
Cancer: An Open Label Phase II Study. J Chemother 2005 Aug 17(4):441-8. 
18. Albers P, Park SI, Niegisch G et al. Randomized phase III trial of 2nd line gemcitabine 
and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus 
prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99].  
Ann Oncol 2011 Feb 22(2):288-94. 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
34 
 
19. Kaufman DS, Winter KA, Shipley WU et al. Phase I-II RTOG Study (99-06) of Patients 
With Muscle-Invasive Bladder Cancer Undergoing Transurethral Surgery, Paclitaxel, 
Cisplatin, and Twice-daily Radiotherapy Followed by Selective Bladder Preservation or 
Radical Cystectomy and Adjuvant Chemotherapy. Urology 2009 73:833-7. 
20. Smith DC, Mackler NJ, Dunn RL et al. Phase II Trial of Paclitaxel, Carboplatin and 
Gemcitabine in Patients With Locally Advanced Carcinoma of the Bladder. J Urol. 2008 
Dec 180(6):2384-8; discussion 2388. 
21. Sousa-Escandon A, Vazquez S, Quintero-Aldana G et al.Neo-adjuvant treatment of 
infiltrating transitional-cell carcinoma of the bladder with paclitaxel and cisplatin: a phase II 
trial. Int J Urol. 2002 Mar 9(3):162-6. 
22. Sanofi-aventis.Sanofi-aventis: XRP6258 investigator’s brochure. Antony (France): s.n., 
2000. 
23. Mita AC, Denis LJ, Rowinsky EK et al.Phase I and pharmacokinetic study of XRP6258 
(RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in 
patients with advanced solid tumors. Clin Cancer Res. 2009 Jan 15(2):723-730. 
24. Villanueva C, Awada A, Campone M.A multicentre dose-escalating study of cabazitaxel 
(XRP6258) in combination with capecitabine in patients with metastatic breast cancer 
progressing after anthracycline and taxane treatment: A phase I/II study. Eur J Cancer. 
2011 May;47(7):1037-45.  
25. Vrignaud, P. Therapeutic synergism of cabazitaxel in combination with cisplatin in 
tumor-bearing mice. American Association for Cancer Research: 102nd Annual 
Conference, 2011. Poster Presentation PO.ET06.01. (Chemotherapeutic Agents). 
26. Sanofi Aventis. A dose-escalation study of the safety, tolerability, and pharmacokinet-
ics of cabazitaxel in combination with cisplatin administered every 3 weeks in subjects with 
advanced solid malignancies. Study Number TCD10870 (Parts 1 and 2).  Submitted for 
publication. 
27. Kaufman DS, Winter KA, Shipley WU et al. Phase I-II RTOG Study (99-06) of Patients 
With Muscle-Invasive Bladder Cancer Undergoing Transurethral Surgery, Paclitaxel, 
Cisplatin, and Twice-daily Radiotherapy Followed by Selective Bladder Preservation or 
Radical Cystectomy and Adjuvant Chemotherapy Urology 2009  Apr 73(4):833-837. 
28. Bochner BH, Kattan MW, Vora KC. Postoperative nomogram predicting risk of 
recurrence after radical cystectomy for bladder cancer. J Clin Oncol 2006 Aug  
24(24):3967-72. 
29. Splinter TA, Scher HI, Denis L et al. The prognostic value of the pathological response 
to combination chemotherapy before cystectomy in patients with invasive bladder cancer. 
European Organization for Research on Treatment of Cancer--Genitourinary Group.  J 
Urol. 1992 Mar 147(3):606-8. 
30. Amendola MA, Glazer GM, Grossman HB, Francis IR.  Staging of Bladder Carcinoma: 
MRI-CT-Surgical Correlation.   Am J Roentgenology 1986 Jun 146:1179-1183. 
31. Takeuchi M, Sasaki S, Ito, M et al. Urinary Bladder Cancer: Diffusion-weighted MR 
Imaging - Accuracy for Diagnosing T Stage and Estimating Histologic Grade. Radiology 
2009 251(1):112-121. 
32. Tekes A, Kamel I, Imam K et al. Dynamic MRI of bladder cancer: Evaluation of Staging 
Accuracy.   Am J Roentgenology 184:121-7. 
33. Dobson MJ, Carrington BM, Collind CD et al. The Assessment of Irradiated Bladder 
Carcinoma Using Dynamic Contrast-enhanced MR Imaging. Clin Radiol. 2001 56:94-99. 
34. Barentsz JO, Jager GJ, van Vierzen PBJ et al. Staging Urinary Bladder Cancer After 
Transurethral Biopsy: Value of Fast Dynamic Contrast-enhanced MR Imaging.  Radiology 
1996 201:185-193. 
35. Tuncbilek N, Kaplan M, Altaner S, et al. Value of Dynamic Contrast-enhanced MRI and 
Correlation with Tumor Angiogenesis in Bladder Cancer.   Am J Roentgenology 2009 Apr 

 
Bristol Bladder Trial Protocol  Version 8.0    01/03/2017 
35 
 
192:949-55. 
36. Schrier BPh, Peters M, Barentsz JO, Witjes JA.Evaluation of Chemotherapy with 
Magnetic Resonance Imaging in Patients with Regionally Metastatic or Unresectable 
Bladder Cancer. Eur Urol 2006 49:698-703. 
37. Huddart RA, James ND, Adab F et al. BC2001: A multicenter phase III randomized trial 
of standard versus reduced volume radiotherapy for muscle invasive bladder cancer 
(ISCRTN:68324339). J Clin Oncol 2009 27(15s):abstr 5022. 
38. Roe K, Muren LP, Rorvik J, et al. Dynamic contrast enhanced magnetic resonance 
imaging of bladder cancer and implications for biological image-adapted radiotherapy. Acta 
Oncologica 2008 47:1257-64. 
39. AJCC 2010 Cancer Staging Manual.  
 
 

 
R1 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 3 RECIST Criteria version 1.1 
 
APPENDIX 1: RECIST CRITERIA version 1.1 
 
Response Evaluation Criteria in Solid Tumours (RECIST) Quick Reference Eligibility  
Only patients with measurable disease at baseline should be included in protocols where objective 
tumour response is the primary endpoint.  
 
Measurable disease: the presence of at least one measurable lesion/lymph node. If the measura-
ble disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytolo-
gy/histology.  
 
Measurable lesions: lesions that can be accurately measured in at least one dimension with 
longest diameter a minimum of size of 10mm by CT scan (CT scan slice no greater than 5mm), 
10mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers are considered non-measurable) or 20mm by chest X-ray.  
 
Bone lesions:  
• 
Bone scan, PET scan or plain films are not adequate imaging techniques to measure 
lesions but can be used to confirm presence or disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic/blastic lesions, with identifiable soft tissue components, 
which can be evaluated using e.g. CT or MRI scan are considered measurable if the 
soft tissue component meets the criteria for measurable lesions described previously.  
• 
Blastic bone lesions are non-measurable.  
 
Cystic lesions:  
• 
Lesions that meet the criteria for radiographically defined simple cysts are not considered 
as malignant lesions.  
• 
‘Cystic lesions’ that are thought to represent cystic metastases are considered measurable 
if they meet the criteria for measurable lesions described previously.   
• 
If non-cystic lesions are present in the same patient then these are preferred for selection 
as target lesions.  
 
Malignant Lymph nodes – to be considered pathologically measurable a lymph node must be 
≥15mm in short axis when assessed by CT scan (CT scan slice thickness no greater than 5mm). 
At baseline and in follow-up, only short axis will be measured and followed.  
 
 
Non-measurable lesions:  all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15mm short axis), i.e. bone lesions, leptomeningeal dis-
ease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cu-
tis/pulmonis, cystic lesions and also abdominal masses that are not confirmed and followed by im-
aging techniques. Lymph nodes to be measured by CT scan >10-<15mm.  
 
Lesions with prior local treatment:  
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other lo-
co-regional therapy are not considered measurable unless progression in the lesion is 
demonstrated.  
 
• 
All measurements should be taken and recorded in metric notation, using a ruler or cali-
pers. All baseline evaluations should be performed as closely as possible to the beginning 
of treatment and never more than 4 weeks before the beginning of the treatment.  
• 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  

 
R2 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 3 RECIST Criteria version 1.1 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by colour 
photography, including a ruler to estimate the size of the lesion, is recommended. Methods 
of Measurement  
• 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Measurability by CT scan is based on the as-
sumption that CT slice thickness is 5mm or less. This applies to tumours of the chest, ab-
domen and pelvis. Head and neck tumours and those of extremities usually require specific 
protocols.  
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumour lesions. It is, however, a possible alternative to clini-
cal measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules. US might also be useful to confirm the complete disappearance of superficial le-
sions usually assessed by clinical examination. If new lesions are identified by US then 
confirmation by CT or MRI is desired.  
• 
The utilization of endoscopy and laparoscopy for objective tumour evaluation is not advised. 
Their uses in this specific context require sophisticated equipment and a high level of ex-
pertise that may only be available in some centres. Therefore, the utilization of such tech-
niques for objective tumour response should be restricted to validation purposes in special-
ized centres. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.  
• 
Tumour markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clini-
cal response when all lesions have disappeared.  
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant le-
sions in tumour types such as germ cell tumours).  
 
Baseline documentation of “Target” and “Non-Target” lesions  
 
• 
All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, rep-
resentative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  
• 
Target lesions should be selected on the basis of their size (lesions with the longest diame-
ter) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  
• 
The short axis of Lymph nodes should be noted since they are normal anatomical struc-
tures which may be visible by imaging.  
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to character-
ize the objective tumour.  
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
 
Documentation of New Lesions  
• 
The presence of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour (for example, some ‘new’ bone lesions may be simply healing or flare of 
pre-existing lesions).  
• 
A lesion identified at a follow-up visit in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  
 
 

 
R3 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 3 RECIST Criteria version 1.1 
 
 
 
Response Criteria 
Evaluation of target lesions 
* Complete Response (CR):  
Disappearance of all target lesions. Patho-
logical lymph nodes (whether target or non-
target) must have reduction in short axis to 
<10mm.  
* Partial Response (PR):  
At least a 30% decrease in the sum of the LD 
of target lesions, taking as reference the 
baseline sum LD  
* Progressive Disease (PD):  
At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the 
smallest sum LD recorded since the treat-
ment started or the appearance of one or 
more new lesions. In addition the smallest 
sum LD must also demonstrate an absolute 
increase of at least 5mm.  
* Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, tak-
ing as reference the smallest sum LD since 
the treatment started  
 
 
Evaluation of non-target lesions 
* Complete Response (CR):  
Disappearance of all non-target lesions and 
normalization of tumour marker level 
*Incomplete Response / Stable Disease (SD):  
Persistence of one or more non-target le-
sion(s) or/and maintenance of tumour mark-
er level above the normal limits  
* Progressive Disease (PD):  
Unequivocal progression of existing non-
target lesions (1). The appearance of one or 
more new lesions is also considered pro-
gression.  
(1) Although a clear progression of “non target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail and the progression status should be confirmed 
later on by the review panel (or study chair).  
 
Lesions that become ‘too small to measure’  
• 
All lesions recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation – even if very small (e.g. 2mm).  
• 
If lesion is reported as ‘too small to measure’ and the radiologist feels the lesion has disap-
peared then the measurement should be recorded as 0mm on the CRF.  
• 
If the lesion is reported as ‘too small to measure’ and is believed to be present but only 
faintly seen then a default value of 5mm should be assigned.  
• 
However, if the radiologist is able to provide an exact measurement, even if below 5mm, 
then this value should be recorded.  
 

 
R4 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 3 RECIST Criteria version 1.1 
 
Evaluation of best overall response  
 
The best overall response is the best response recorded from the start of the treatment until dis-
ease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
 
The table below provides a summary of the overall response calculation at each time point. 
 
Target lesions  
Non-Target le-
sions  
New Lesions  
Overall response  
CR  
CR  
No  
CR  
CR  
Incomplete re-
sponse/SD  
No  
PR  
CR  
Not-evaluated*  
No  
PR  
PR  
Non-PD or not all 
evaluated  
No  
PR  
SD  
Non-PD or not all 
evaluated  
No  
SD  
Not all evaluated  
Non-PD  
No  
Not evaluable  
PD  
Any  
Yes or No  
PD  
Any  
PD  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
 
* When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time 
point. If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE at 
that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would 
not change the assigned time point response.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after dis-
continuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response sta-
tus.  
 
Confirmation  
• 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed.  
• 
To be assigned a status of PR or CR, changes in tumour measurements must be confirmed 
by repeat assessments that should be performed no less than four weeks after the criteria 
for response are first met. Longer intervals as determined by the study protocol may also 
be appropriate.  
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once af-
ter study entry at a minimum interval (in general, not less than six-eight weeks) that is de-
fined in the study protocol  
 
Duration of overall response  
• 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started.  

 
R5 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 3 RECIST Criteria version 1.1 
 
Duration of stable disease  
• 
SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
• 
The clinical relevance of the duration of SD varies for different tumour types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval re-
quired between two measurements for determination of SD. This time interval should take 
into account the expected clinical benefit that such a status may bring to the population un-
der study.  
 
Response review  
• 
For trials where the response rate is the primary endpoint it is strongly recommended that 
all responses be reviewed by an expert(s) independent of the study at the study’s comple-
tion. Simultaneous review of the patients’ files and radiological images is the best ap-
proach.  
 
Reporting of results  
• 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be as-
signed one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) Inevaluable for response: specify reasons (early death, 
malignant disease; early death, toxicity; tumour assessments not repeated/incomplete; oth-
er (specify))  
• 
All of the patients who met the eligibility criteria should be included in the main analysis of 
the response rate. Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-9 will be protocol specific.  
• 
All conclusions should be based on all eligible patients.  
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other rea-
sons, early discontinuation of treatment, major protocol violations, etc.). However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment effi-
cacy, and the reasons for excluding patients from the analysis should be clearly reported.  
• 
The 95% confidence intervals should be provided.  

 
G1 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 4 Measurement of GFR 
APPENDIX 2: MEASUREMENT OF GFR  
 
Estimated GFR is required. The recommended technique is eGFR using the CKD-EPI formula ac-
cording to the table below: 
 
 
Race and Sex 
Serum Creati-
nine Level, 
µmol/L (mg/dl) 
Equation 
Black 
Female 
≤62 (≤0.7) 
GFR = 166 x (SCr/0.7)-0.329 x (0.993)Age 
>62 (>0.7) 
GFR = 166 x (SCr/0.7)-1.209 x (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 163 x (SCr/0.9)-0.411 x (0.993)Age 
>80 (>0.9) 
GFR = 163 x (SCr/0.9)-1.209 x (0.993)Age 
White or other 
Female  
≤62 (≤0.7) 
GFR = 144 x (SCr/0.7)-0.329 x (0.993)Age 
>62 (>0.7) 
GFR = 144 x (SCr/0.7)-1.209 x (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 141 x (SCr/0.7)-0.411 x (0.993)Age 
>80 (>0.9) 
GFR = 141 x (SCr/0.7)-1.209 x (0.993)Age 
: 
  
 
▪ 
An acceptable alternative is direct measurement using 51Cr-labelled EDTA clearance which is 
recommended for patients with borderline renal function (see main text).  Where the CKD-EPI 
formula produces a result that is lower than 60ml/min, a result of >60ml/min from this method 
should be regarded as the more accurate estimate.  
 
 
 
Reference 
 
Levey AS, Stevens LA, Schmid CH et al. for the CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration) A New Equation to Estimate Glomerular Filtration Rate Ann 
Intern Med. 2009;150:604-612.

 
S1 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 5 Study Drug (Cabazitaxel) product information and 
handling 
APPENDIX 3:  STUDY DRUG (CABAZITAXEL) PRODUCT INFORMATION AND 
HANDLING  
Cabazitaxel: 
 
Cabazitaxel is supplied for parenteral administration as a sterile, non-pyrogenic non-
aqueous solution contained in a 15 ml clear glass vial closed with a rubber closure. The 
closure is crimped to the vial with an aluminium cap covered with a light green plastic flip-
off cap.  
 
The solution is clear and yellowish to brownish-yellow.  
 
Each vial contains 60 mg of cabazitaxel, expressed on anhydrous and solvent-free basis, 
per 1.5 ml of solution.  
 
The fill volume has been established to include an overfill [i.e., 1.5 ml (nominal volume) + 
0.33 ml]. This overfill was determined to ensure that a 10 mg/ml (corresponding to 60 
mg/ml) concentration is obtained in the premix and that 60 mg dose can be extracted. 
This must be done with the entire contents [i.e., 4.5 ml (nominal volume) + 1.17 ml) of the 
solvent for dilution for cabazitaxel. 
 
 
 
Solvent vial: 
 
The solvent used for the preparation of the premix is a sterile, non-pyrogenic solution 
containing a 13 % w/w ratio of ethanol 95 % in water for injection. This solution is 
contained in a 15 mL clear type I glass vial closed with a rubber closure. The closure is 
crimped to the vial with either an aluminum cap covered with a light grey plastic flip-off cap 
or a gold-color aluminum cap covered with a colorless plastic flip off cap.  
The solution is a clear colorless liquid.  
 
Each vial is overfilled to ensure that a 10 mg/mL concentration is obtained in the Premix 
and that 60 mg dose can be extracted. [i.e., 4.5 mL (nominal volume) + 1.17 mL] . 
 
Excipients: 
Polysorbate 80 from vegetable origin, for the drug product vial.  
Water for injection and ethanol for the solvent vial. 
Storage conditions: 
Vials should be stored according to their labeling and kept in their kit until use. 

 
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Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 5 Study Drug (Cabazitaxel) product information and 
handling 
Preparation 
Cabazitaxel drug products should be administered only by intravenous route. 
It is supplied as a kit containing one single-use vial of cabazitaxel concentrate for solution 
for infusion and one single vial of solvent for dilution. The administration of the product 
requires two dilutions prior to administration. 
 
This pharmaceutical dosage form is a concentrate for solution for infusion and must be 
diluted before administration. First the dosage form is diluted with the solvent supplied 
(preparation of the “cabazitaxel premix solution”). Then this premix solution must be 
diluted in an infusion vehicle (preparation of the “cabazitaxel infusion solution”). Each 
cabazitaxel vial and each corresponding solvent vial are overfilled to ensure that a 60 mg 
dose can be withdrawn after the preparation of the premix. 
 
Preparation of cabazitaxel premix solution under aseptic conditions: 
Use one solvent vial per each vial of cabazitaxel concentrate.  
 
Withdraw, under aseptic conditions, the entire contents of the solvent vial and inject it into 
the corresponding vial of cabazitaxel concentrate. Gently mix the reconstituted solution by 
repeated inversions for at least 45 seconds until obtaining clear and homogenous solution.  
Do not shake. Let the premix solution stand for a few minutes at room temperature to 
allow foam to dissipate. The solution is homogeneous and contains no visible particulate 
matter. It is normal for foam to persist after this time period. 
 
In order to compensate for liquid loss during preparation and to ensure that the JEVTANA 
initial diluted solution (premix) can be prepared at the concentration of 10 mg/ml and that a 
nominal volume of at least 6 ml can be withdrawn from the premix vial, the JEVTANA 60 
mg/1.5 ml concentrate vials are filled with a 22% overfill (total fill volume 1.83  ml) and the 
diluent vials with a 26% overfill (total fill volume 5.67 ml). 
  
The concentration of 10 mg/ml in the premix [60mg/1.5 ml (concentrate) + 4.5 ml (diluent)] 
can be calculated as follows taking into account the overfilling: 73.2mg/ 1.83 ml (22 % 
overfill concentrate) + 5.49 ml  (overfill diluent *) = 10 mg/ml 
              
     
Thus, the preparation obtained ensures a minimal extractable volume of the premix 
solution of 6 ml corresponding to a concentration of 10 mg/ml of cabazitaxel corresponding 
to 60mg/6 ml.  
 
Preparation of cabazitaxel infusion solution under aseptic conditions: 
WARNING: Since foam is normally present, the required dose must be accurately 
adjusted using a graduated syringe.  
 
Withdraw, under aseptic conditions, the volume of the premix solution containing 10 mg/ml 
of cabazitaxel that corresponds to the required dose (mg) and inject the required premix 

 
S3 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 5 Study Drug (Cabazitaxel) product information and 
handling 
volume into a 125 to 500 ml infusion container (either 5 % glucose solution for injection or 
0.9 % sodium chloride solution for injection). Mix the content of the infusion container 
manually by gently inverting the bag or bottle. The concentration of the infusion should be 
between 0.10 mg/ml and 0.26 mg/ml (based on Maximum Tolerated Dose of 30 mg/m² and 
a Body Surface Area of 2.1 m²). 
 
Infusion conditions:  
The recommended infusion duration is one hour. The infusion solution should be used  
within 8 hours at ambient temperature (including the one hour infusion time) or within a 
total of 48 hours if refrigerated (including the one hour infusion time). 
The infusion solution should be administered at room temperature under normal lighting 
conditions. 
 
• Do not use PVC infusion containers for cabazitaxel preparation and 
administration. 
• Do not use polyurethane infusion sets for cabazitaxel preparation and 
administration 
 
Glass bottles could also be used.  
Use an in-line filter of 0.22 μm nominal pore size (also referred to as 0.2 μm) during 
cabazitaxel administration. 
 
Shelf life: 
Cabazitaxel premix solution  
Premix solution should be used immediately after preparation and within 1 hour at ambient 
temperature. 
 
Cabazitaxel infusion solution  
The infusion solution is stable for 8 hours at ambient conditions (including the 1 hour 
infusion time) or a total of 48 hours if refrigerated, from preparation to end of infusion.  
 
Recommendation for the safe handling:  
Cabazitaxel is an antineoplasic agent and, like other potentially toxic compounds, caution 
should be exercised in handling and preparing cabazitaxel solutions. The use of gloves is 
recommended.  
If cabazitaxel concentrate, premix solution or infusion solution should come into contact 
with skin, wash immediately and thoroughly with soap and water. If cabazitaxel 
concentrate, premix solution, or infusion solution should come into contact with mucous 
membranes, wash immediately and thoroughly with water. 

 
Q1 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
APPENDIX 4:  
Quality of Life Questionnaires: 
 
EORTC QLQ C30 and supporting module BLM 30  
 
 
 
 
 
EQ-5D 5L

 
Q2 
Bristol Bladder Trial 8.0  01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 

 
Q3 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 

 
Q4 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
  

 
Q5 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
 

 
Q6 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the UK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 

 
Q7 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
 
 
Under each heading, please tick the ONE box that best describes your health TODAY  
 
MOBILITY 
I have no problems in walking about  
 
 
 
❑ 
I have slight problems in walking about  
 
 
 
❑ 
I have moderate problems in walking about  
 
 
❑ 
I have severe problems in walking about  
 
 
 
❑ 
I am unable to walk about  
 
 
 
 
 
❑ 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
❑ 
I have slight problems washing or dressing myself   
 
❑ 
I have moderate problems washing or dressing myself  
 
❑ 
I have severe problems washing or dressing myself  
 
❑ 
I am unable to wash or dress myself   
 
 
 
❑ 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
❑ 
I have slight problems doing my usual activities  
 
 
❑ 
I have moderate problems doing my usual activities  
 
❑ 
I have severe problems doing my usual activities   
 
❑ 
I am unable to do my usual activities  
 
 
 
❑ 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
❑ 
I have slight pain or discomfort  
 
 
 
 
❑ 
I have moderate pain or discomfort   
 
 
 
❑ 
I have severe pain or discomfort  
 
 
 
 
❑ 
I have extreme pain or discomfort   
 
 
 
❑ 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
❑ 
I am slightly anxious or depressed   
 
 
 
❑ 
I am moderately anxious or depressed  
 
 
 
❑ 
I am severely anxious or depressed   
 
 
 
❑ 
I am extremely anxious or depressed  
 
 
 
❑ 
 
UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 

 
Q8 
Bristol Bladder Trial version 8.0 01/03/2017 APPENDIX 6 Quality of Life Questionnaires 
 
 
 
 
We would like to know how good or bad your health is  TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY.  
• Now, please write the number you marked on the scale in the box be-
low.  
                     
 
 
 
YOUR HEALTH TODAY  = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health       
 you can imagine 
The worst health     
 you can imagine 

  
Bristol Bladder Trial version 8.0 (01/03/2017) APPENDIX 7 CYP3A inhibitors + inducers 
Y1 
 
APPENDIX: 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
Bristol Bladder Trial version 7. 4  01/03/2017 7 CYP3A inhibitors + inducers 
Y2 
 
 
LIST OF INDUCERS BY CYP3A ISOENZYMES 
 
 
 
 
 

  
L1 
Bristol Bladder Trial version 8.0  01/03/2017APPENDIX 9 GP information letter