Conditions: Metastatic Seminoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
This study evaluated the safety, efficacy and toxicity of carboplatin area under the curve (AUC)-10 in metastatic seminoma to see if, by using fluoro-deoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) to assess metabolic response, the number of patients requiring 4 cycles can be reduced. Carboplatin AUC-10 was given every 21 days. A PET-CT scan was carried out on day 17-21 of the first cycle. If the PET - CT scan showed a complete response patients received 3 cycles of treatment. If the PET - CT scan did not show a complete response patients received 4 cycles of treatment. After treatment, patients were followed up for 2 years.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Carboplatin AUC-10
Intervention descriptions: intervention 1: Carboplatin AUC-10 according to the Calvert formula \[10 x (glomerular filtration rate (ml/min) + 25)\]mg given in 5% glucose over 1 hour every 21 days for 3 or 4 cycles.

Protocol document:
Prot_000.pdf: 
 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     Page 1 of 54 
 
 
 
 
A MULTI-CENTRE PHASE II STUDY USING CARBOPLATIN AUC-10 FOR 
METASTATIC SEMINOMA WITH IGCCCG GOOD PROGNOSIS DISEASE – 
THERAPY DIRECTED BY INITIAL METABOLIC RESPONSE ON PET-CT 
[Car-PET] 
 
Version: 8.0 dated 31 Aug 2017 
EudraCT Number: 2009-009882-33 
Protocol number: TE 2010 11 
REC: 10/H0703/45 
 
 
PLEASE DESTROY PREVIOUS VERSIONS 
[RETAINING A SINGLE COPY IN YOUR TRIAL SITE FILE] 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chief Investigator: 
Dr Jonathan Shamash, MD FRCP 
Consultant Medical Oncologist 
Barts Cancer Institute - a CR-UK Centre of Excellence 
Centre for Experimental Cancer Medicine 
Barts and The London School of Medicine and Dentistry 
Lower Ground Floor, Old Anatomy Building 
Charterhouse Square 
LONDON UK EC1M 6BQ 
 
Tel:  
 
 
020 3465 7108   
Fax:  
 
 
020 7882 8409 
Email:   
 
bci-carpet@qmul.ac.uk  
Sponsor: 
Barts Health NHS Trust 
Representative  
of sponsor:  
Sally Burtles 
 
 
Director of Research Services & Business Development 
Address: 
Joint Research Management Office 
 
 
Queen Mary’s Innovation Centre 
Lower Ground Floor 
5 Walden Street 
London E1 2EF 
 
Tel: 
 
020 7882 7250 
Fax: 
 
020 7882 7276 
Email:  
sponsorsrep@bartshealth.nhs.uk  
 



 
Page 2 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
STUDY CONTACTS 
 
 
 
Chief Investigator 
Dr Jonathan Shamash  
Consultant Medical Oncologist 
Barts Cancer Institute - a CR-UK Centre of 
Excellence 
Barts Health NHS Trust 
Queen Mary’s School of Medicine and Dentistry 
7th Floor Gloucester House 
St Bartholomew’s Hospital 
Little Britain 
London EC1A 7BE 
 
Tel: 0203 465 7108   
Fax: 0207 882 8409 
Email: jonathan.shamash@bartshealth.nhs.uk 
Collaborator/s: 
Dr. Jamshed B. Bomanji MBBS, PhD, FRCR, 
FRCP 
Head of the Department  
Institute of Nuclear Medicine, T5 
University College Hospital  
Radiotherapy Basement 
35 Euston Rd 
London NW1 2BU 
 
 
Tel:  0203-447-0528  
Tel:  0203-456-7890 ext 70527 
Fax: 0203-447-0596  
Email: jamshed.bomanji@uclh.nhs.uk 
 
 
Study Statistician:  
Dr Shah-Jalal Sarker  
Lecturer in Cancer Biostatistics 
Centre for Experimental  
Cancer Medicine 
Barts Cancer Institute – a CR-UK Centre of 
Excellence 
Queen Mary University of London  
Lower Ground Floor, Old Anatomy Building 
Charterhouse Square 
LONDON UK EC1M 6BQ 
 
Tel: 0207 882 8495  
Fax: 0207 882 8409 
Email: s.sarker@qmul.ac.uk 
 
Car-PET Trial Coordinator: 
Centre for Experimental Cancer Medicine 
Barts Cancer Institute – a CR-UK Centre of 
Excellence 
Queen Mary University of London 
Lower Ground Floor 
Old Anatomy Building 
Charterhouse Square 
LONDON UK EC1M 6BQ 
Tel:  0207 882 8487 
Fax: 0207 882 8409 
Email: bci-carpet@qmul.ac.uk 
 
 
CENTRAL FACILITIES 
 
Samples for future research: 
Orchid Tissue Bank Manager 
Orchid Tissue Bank 
Centre for Experimental Cancer Medicine 
Barts Cancer Institute - a CR-UK Centre of 
Excellence 
Queen Mary University of London 
John Vane Science Centre 
Charterhouse Square 
LONDON EC1M 6BQ 
 
Tel: 0207 882 3845 
Central review of PET scans: 
Dr Rizwan Syed 
Head of the Department  
Institute of Nuclear Medicine, 
University College Hospital  
235 Euston Road  
London NW1 2BU  
 
Tel:  0203-447-0528  
Tel:  0203-456-7890 ext 70527 
Fax: 0203-447-0596  
Email: rizwansyed@nhs.net  



 
Page 3 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
PROTOCOL SIGNATURE PAGE 
 
Signature of the Chief Investigator:  
 
The clinical study as detailed within this research protocol (version 8.0, dated 31 Aug 2017), and any 
subsequent amendments, involves the use of an investigational medicinal product and will be conducted in 
accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical 
Association Declaration of Helsinki (1996), Principles of ICH-GCP, and the current regulatory requirements, 
as detailed in the Medicines for Human Use (Clinical Trials) Regulations 2004 (UK S.I. 2004/1031) and any 
subsequent amendments of the clinical trial  regulations. 
 
Chief Investigator Name:  
 
Dr. Jonathan Shamash 
 
Signature and Date: 
 
 
                                              a  
 
 
 
 
 
 
3 1 / A U G / 2 0 1 7 
 
Statistician Agreement 
 
The Car-PET clinical study as detailed within this research protocol (version 8.0, dated 31 Aug 2017), or any 
subsequent amendments, involves the use of an investigational medicinal product and will be conducted in 
accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical 
Association Declaration of Helsinki (1996),  Principles of ICH E6-GCP, ICH E9 -  Statistical principles for 
Clinical Trials, ICH E10 - Choice of Control Groups and the current regulatory requirements, as detailed in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (UK S.I. 2004/1031) and any subsequent 
amendments of the clinical trial regulations. Signature of the Principal Investigator:  
 
Statistician Name: 
 
 
Dr Shah-Jalal Sarkar 
 
 
Signature and Date: 
 
 
_______________________________________ 
 
 
 
 
 
 
3 1 / A U G / 2 0 1 7 
 
Signature of the Principal Investigator 
 
The clinical study as detailed within this research protocol (version 8.0, dated 31 Aug 2017), and any 
subsequent amendments, involves the use of an investigational medicinal product and will be conducted in 
accordance with the Research Governance Framework for Health & Social Care (2005), the World Medical 
Association Declaration of Helsinki (1996), Principles of ICH-GCP, and the current regulatory requirements, 
as detailed in the Medicines for Human Use (Clinical Trials) Regulations 2004 (UK S.I. 2004/1031) and any 
subsequent amendments of the clinical trial regulations. 
 
Principal Investigator Name: 
 
_________________________________________________ 
 
Principal Investigator Site:      
 
________________________________________________ 
 
Signature and Date: 
 
_ 
_________________________________________________ 
 
 __ __ / __ __ __ / __ __ __ __ 



 
Page 4 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 Contents 
 
1.0 
Introduction ................................................................................................. 9 
1.1 
Background .............................................................................................. 9 
1.2 
Investigational agent ................................................................................ 9 
1.3 
Clinical data to date ............................................................................... 10 
2.0 
Study aims and objectives ........................................................................ 10 
3.0 
Investigational plan ................................................................................... 11 
3.1 
Overall design ........................................................................................ 11 
3.2 
Treatment plan ....................................................................................... 11 
3.3 
Study population .................................................................................... 15 
3.4  Target accrual ........................................................................................ 15 
4.0 
Eligibility, subject selection and withdrawal ............................................... 15 
4.1 
Inclusion Criteria .................................................................................... 15 
4.2 
Exclusion Criteria ................................................................................... 15 
4.3 
Subject recruitment and screening ........................................................ 15 
4.4 
Withdrawal of subjects ........................................................................... 16 
4.4.1 
Data collection and follow up for withdrawn subjects ...................... 16 
5.0  
Study procedures and schedule of assessments ...................................... 17 
5.1 
Informed consent procedures ................................................................ 17 
5.2 
Registration/study procedures ............................................................... 17 
5.3 
Treatment procedures ............................................................................ 18 
5.3.1 
Pre-treatment investigations ............................................................ 18 
5.3.3 
Central review of PET-CT scans ..................................................... 19 
5.4 
Study Flowchart ..................................................................................... 22 
5.5 
Follow up ............................................................................................... 24 
6.0 
Investigational Medicinal Product(s)/treatment details .............................. 24 
6.1 
Description of IMP.................................................................................. 24 
6.2 
Product sourcing manufacture and supply ............................................. 24 
6.3 
Pre-Medication ....................................................................................... 24 
6.4 
Prescription of IMP ................................................................................ 24 
6.5 
Preparation and administration of IMP ................................................... 25 
6.6 
Prior and concomitant therapies ............................................................ 25 
6.6.1 Recording concomitant medications ................................................... 26 
6.7 
Dose modification/reduction/delay ......................................................... 29 
6.8  Toxicity profiles ...................................................................................... 29 
6.9 
Labelling/Packaging ............................................................................... 29 
6.10 
Blinding of IMP ................................................................................... 29 
6.11 
Receipt of IMP supplies/Storage ........................................................ 29 
7.0 
Pharmacovigilance .................................................................................... 30 
7.1 
General definitions ................................................................................. 30 
7.1.1 
Adverse Event (AE) ......................................................................... 30 
7.1.2 
Adverse Reaction (AR) .................................................................... 30 
7.1.3 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 30 
7.1.4 
Suspected Unexpected Serious Adverse Events - SUSAR’s .......... 31 


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Page 5 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
7.3 
Notification and reporting adverse events or reactions .......................... 32 
7.4 
Notification and reporting of serious adverse events/SUSAR ................ 32 
7.6 
Expected SAEs/SARs ............................................................................ 33 
7.7 
Pregnancy .............................................................................................. 33 
7.8 Urgent Safety Measures ............................................................................ 34 
8 
Annual Reports ............................................................................................ 35 
8.1 
Development Safety update reports (DSURs) and Annual Progress 
Reports (APRs) ............................................................................................... 35 
9 
Data handling and record keeping ............................................................... 35 
9.1 
Confidentiality ........................................................................................ 35 
9.2 
Essential Study documents .................................................................... 35 
9.3 
Case Report Forms................................................................................ 36 
9.4 
Record retention and archiving .............................................................. 36 
9.5 
Compliance ............................................................................................ 36 
10 Governance Issues ...................................................................................... 37 
10.1 
Risk Assessment ................................................................................ 37 
10.2  
Summary Monitoring Plan .................................................................. 37 
Original CRFs will be sent by post from site to the trial coordinator/monitor in a 
timely manner.  Upon receipt of CRFs the trial coordinator/monitor will review 
for any obvious errors and data queries will be raised. ................................... 38 
10.3 
Audit and Inspection ........................................................................... 38 
10.4 
Serious breaches in GCP or study protocol ........................................ 38 
10.5 
Quality Assurance .............................................................................. 39 
10.6 
Ethical Considerations ........................................................................ 39 
10.7 
Trial Committees ................................................................................ 40 
10.7.1 Trial Steering Committee (TSC) ...................................................... 40 
10.7.2 Trial Management Group (TMG) ..................................................... 40 
11 Statistics ...................................................................................................... 41 
11.1 Endpoints ................................................................................................ 41 
11.1.1 Primary Endpoints ........................................................................... 41 
11.1.2 Secondary Endpoints ...................................................................... 41 
11.1.3 Definition of end of study ................................................................. 41 
11.2 
Statistical considerations .................................................................... 41 
11.2.1 Sample Size .................................................................................... 41 
11.2.2  
Planned recruitment rate .............................................................. 42 
11.3 
Statistical Analysis .............................................................................. 42 
11.4 
Frequency of analysis ......................................................................... 42 
11.5 
Primary endpoint analysis .................................................................. 43 
11.6 
Secondary endpoint analysis .............................................................. 43 
11.7 
Interim analysis ................................................................................... 43 
12 Sponsorship and Indemnity ......................................................................... 43 
13 Publication policy ......................................................................................... 43 
14 References .................................................................................................. 45 
15 Appendices .................................................................................................. 46 
 
 



 
Page 6 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
GLOSSARY OF TERMS AND ABBREVIATIONS 
 
 
AE 
 
Adverse Event  
AFP 
 
Alpha-fetoprotein 
AR 
 
Adverse Reaction 
AUC 
 
Area under the Curve 
BEP 
 
Bleomycin, Etoposide, Cisplatin 
CI 
 
Chief Investigator 
CIOMS  
Council for International Organizations of Medical Sciences 
CR 
 
Complete Response  
CRF 
 
Case Report Form  
CT 
 
Computed Tomography  
CTCAE  
Common Terminology Criteria for Adverse Events 
ECOG  
Eastern Cooperative Oncology Group  
EDTA  
Ehylenediaminetetraacetic acid 
EU 
 
European Union 
 
FAS 
 
Full Analysis Set 
FDG 
 
Fluorodeoxyglucose 
FSH 
 
Follicle-stimulating hormone 
GCP 
 
Good Clinical Practice 
GCSF  
Granulocyte Colony-Stimulating Factor  
GFR 
 
Glomerular Filtration Rate 
hCG 
 
Human Chorionic Gonadotropin  
ICH 
 
International Council for Harmonization 
IEC 
 
Independent Ethics Committee 
IGCCCG 
International Germ Cell Cancer Collaborative Group  
IMP 
 
Investigational medicinal product 
JRO 
 
Joint Research Office 
LDH 
 
Lactate Dehydrogenase 
LFTs 
 
Liver Function Tests  
LH 
 
Luteinizing hormone 
MDT 
 
Multidisciplinary Team Meeting 
ml/min  
millilitre/minute  
MRC 
 
Medical Research Council 
MREC  
Multi Research Ethics Committee  
NHS 
 
National Health Service 
OCTG  
Orchid Clinical Trials Group 
PD 
 
Progressive Disease  
PET 
 
Positron Emission Tomography  
PFS 
 
Progression Free Survival  
PI 
 
Principal Investigator  
PR 
 
Partial Response  
PS 
 
Performance Status  
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction  
SD 
 
Stable Disease  
SOP 
 
Standard operating procedure 
SPD 
 
Sum of Produce of the Diameters  
SS 
 
Safety Set  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
SUV 
 
Standard Uptake Value 
U&Es  
Urea and Electrolytes  
WBC 
 
White Blood Count  
 
 
 



 
Page 7 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
Protocol Synopsis 
 
Title 
A multi-centre phase II study using carboplatin AUC-10 for metastatic 
seminoma with IGCCCG good prognosis disease – therapy directed by initial 
metabolic response on PET-CT. 
Short Title 
Car-PET 
Protocol Version 
Number and Date 
Version 8.0 (31 Aug 2017)  
Methodology 
This is a single arm phase II trial to assess the safety, efficacy and toxicity of 
carboplatin AUC-10 in metastatic seminoma.  Patients will be recruited from 2 
sites. 
Study duration 
48 months for recruitment.  2 years for follow up. 
Study centres 
Multisite. 
Objectives 
 
To assess the safety, efficacy and toxicity of carboplatin AUC-10 in 
metastatic seminoma in a multi-centre setting. 
 
To see if the number of patients requiring 4 cycles can be reduced by the 
use of FDG PET-CT in the assessment of metabolic response.  
Phase of Trial 
II 
Number of patients 
Up to 50 patients will be recruited into the study over four years (assuming 5 
patients may drop out for reasons other than disease progression).  45 
evaluable patients will be necessary to establish activity of Carboplatin AUC10 
in this setting. 
Inclusion criteria 
1. 
Metastatic seminoma-IGCCCG good prognosis. 
2. 
Glomerular filtration rate of over 25 ml/min (creatinine clearance should 
preferably be assessed using an EDTA clearance). 
3. 
ECOG performance status 0-3. 
4. 
Normal Alpha-fetoprotein (All levels of Human chorionic gonadotropin 
and lactate dehydrogenase are acceptable). 
5. 
Males aged greater than 18 and less than 75 years. 
6. 
Able to give written informed consent prior to study entry. 
7. 
Patients must be sterile or agree to use adequate contraception during 
the period of therapy. 
Exclusion criteria 
1. 
Metastatic seminoma with any non-pulmonary visceral metastases. 
2. 
Raised Alpha-fetoprotein. 
3. 
Any previous chemotherapy or radiotherapy. 
4. 
Currently enrolled in any other investigational drug study. 
5. 
Other malignancy except basal cell. 


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Page 8 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
Statistical 
Methodology and 
Analysis 
The primary efficacy endpoint is the Progression Free Survival (PFS) rate at 2 
years from completion of treatment.  Patients who do not complete 2 years 
follow-up for reasons other than death will be censored at the last date of 
follow-up.  The PFS rate will be determined for the Carboplatin AUC-10, along 
with a 95% confidence interval, and the Kaplan-Meier curves will be plotted.  
The trial result will be considered positive if the PFS rate for patients on 
Carboplatin AUC-10 demonstrates an increase in survival of 15% or more 
when compared to PFS rates of standard chemo i.e. if there are at least 39 
PFS patients out of first 45 patients at 2 years. 
 
Subgroup analyses of the PFS rate will be performed in terms of patients with 
complete or partial response at 2 years.  The analysis of safety will include all 
patients who received at least one cycle of treatment.  Safety and tolerability of 
Carboplatin AUC-10 will be determined by an evaluation of changes in 
laboratory parameters, vital signs, the incidence and severity of Adverse 
Events and of toxicities according to the CTCAE classification (version 4.03).  
The proportion of patients at each toxicity grade (0 to 4) of any type (including 
vomiting, nausea and diarrhoea) will be summarised.  Safety analysis will be 
performed based on safety data set. 
 
Metabolic response rate will be assessed as described in section 5.3.3 of the 
protocol. 



 
Page 9 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
1.0 
Introduction 
1.1 
Background 
 
Metastatic seminoma is a relatively infrequent disease entity.  The conventional treatment 
for it, namely cisplatin and etoposide with or without bleomycin, has a progression free 
survival rate at 3 years of over 81% compared to 71% treated with Carboplatin AUC 7 [1].  
The overall survival however, is identical due to the effectiveness of second line salvage 
chemotherapy.  The conventional treatment is toxic, usually requires an inpatient stay with 
administration over 3 days and can cause significant nausea, malaise, alopecia, risk of 
renal damage, hypertension and high tone hearing loss.  It is possible to give this 
treatment on an outpatient basis however, this can be inconvenient as the patient has to 
attend for prolonged visits to a chemotherapy day ward for a minimum of 3 consecutive 
days for each cycle of treatment.  Single agent carboplatin does not appear to have long 
term renal and hearing problems.  There is no alopecia.  Nausea and malaise are much 
less common and the treatment can be given as a day case with only one visit to hospital 
for one hour per cycle they receive.  
 
1.2 
Investigational agent 
 
A variety of observations have led to the impression that seminomas are inherently more 
chemo-sensitive than non-seminomatous germ cell tumours.  Several studies have 
addressed the use of single agent carboplatin in metastatic seminoma.  Studies have 
generally concluded that although progression free survival is inferior to that seen with 
cisplatin based therapy, as a large number of relapsing patients could be salvaged, the 
overall survival was unchanged and indeed toxicity was substantially reduced [1, 2].  There 
is clear evidence for a dose response curve to platinum drugs in germ cell tumours; 
although certainly in metastatic non-seminomatous tumours there is little evidence to 
support intensification from AUC-5 to AUC-8 [3, 4].  In other tumour types notably epithelial 
carcinoma of the ovary, higher doses of carboplatin (AUC-12) have proved feasible 
although the increasing dose intensity has been smaller than anticipated because of 
delays in retreating patients due to the prolonged myelosuppression [5].  
 
 



 
Page 10 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
1.3 
Clinical data to date 
 
The Orchid Clinical Trials Group recently completed a study in metastatic seminoma using 
carboplatin AUC-10.  Twenty patients received this dose of carboplatin for metastatic 
seminoma, with a median follow up of 29.4 months.  Following the closure of the study a 
further 20 patients have received carboplatin AUC-10.  In total 40 patients have been 
treated.  There have been 2 relapses to date (5%), compared to the 18% relapse seen 
within the first 2 years of treatment of 28 patients who received AUC 7 or less with a 
median follow up of 135 months. 
 
The relapsed patients were successfully salvaged using conventional chemotherapy. As 
nearly all relapses occur within 2 years of therapy, a 2 year progression-free survival is an 
appropriate endpoint for this phase II study. 
 
In this most recent study, the protocol stipulated that all patients who were not in complete 
remission by day 21 of the first cycle would receive 4 rather than 3 cycles.  This led to all 
those who essentially had greater than 2B disease requiring 4 cycles.  This was probably 
unnecessary as most patients achieved a CR eventually – it just took time for the masses 
to shrink.  
 
It is hoped that by substituting conventional CT for PET CT a greater proportion of patients 
will achieve a complete metabolic response and therefore the 4th cycle may be avoided in 
more patients.  This will allow shortening of the treatment and reduction in the use of blood 
products as most of the blood transfusions required occur during the 4th cycle of 
carboplatin.    
2.0 
Study aims and objectives 
 
 
To assess the safety, efficacy and toxicity of carboplatin AUC-10 in metastatic 
seminoma in a multi-centre setting. 
 
To see if, by using FDG PET-CT to assess metabolic response, the number of 
patients requiring 4 cycles can be reduced. 
 
 



 
Page 11 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
2.1 
End points 
 
Primary  
2-year progression free survival 
 
Secondary 
Metabolic response rate 
Overall survival 
Toxicity level (CTCAE version 4.03) 
3.0 
Investigational plan 
3.1 
Overall design 
 
This is a single arm phase II study to assess the safety, efficacy and toxicity of carboplatin 
AUC-10 in metastatic seminoma.  Patients will be recruited from two sites.   
Prior to the commencement of treatment, the patient should have a baseline PET-CT scan 
and a contrast enhanced CT scan performed within 28 days of study entry.  Patients will 
be treated with carboplatin AUC-10 every 3 weeks (3 weeks=1 cycle) and on day 17-21 
of the first cycle a repeat PET-CT scan will be performed.  All PET-CT scans will be 
reviewed centrally and these results will determine how many further treatment cycles the 
patients will undergo.  If the patient has a complete metabolic response [refer to Appendix 
3], a further 2 cycles of carboplatin will be given, leading to a total of 3, and if the patient 
has not had a complete metabolic response but is responding, a further 3 cycles of 
carboplatin will be given [Refer to section 5.3.3 and page 20 (the table) for the timelines 
for the scans.  Please refer to appendix 8 for the imaging protocol].     
 
If no response is seen, then the patient will be taken off study and will receive conventional 
therapy using a cisplatin-based combination. 
 
All PET CT scans will be performed at (or sent to) University College Hospital to be 
centrally reviewed. 
3.2 
Treatment plan 
 
Carboplatin will be administered as a day case and doses will be calculated using the 
Calvert formula as below: 
Dose (mg) = (GFR + 25) x 10 



 
Page 12 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
Unless dictated by haematological toxicity, the Carboplatin dose should not be 
recalculated for each cycle.  However, if the serum Creatinine has risen by > 20% above 
baseline, the Carboplatin dose must be recalculated using the Calvert formula with GFR 
determined by EDTA clearance.  At the discretion of the PI an estimated creatinine 
clearance can be calculated using e.g. Cockcroft and Gault (or as per local policy) if the 
site is unable to obtain EDTA clearance. 
 
Treatment will be repeated every 3 weeks (when platelets over 100 x 109/L, white blood 
count greater than 3x109/L or neutrophils greater than 1x109/L).   
 
If the blood count is below the level required to commence the next cycle of treatment (i.e. 
platelets less than 100 x 109/, white blood count less than 3 x 109/L or neutrophils less 
than 1 x 109/L) then a further blood count must be repeated 48 hours after the target 
treatment day.  If the results of this repeat count show platelets greater than 75 x 109/L 
and rising, white blood count greater than 3 x 109/L or the neutrophils greater than 1 x 
109/L the patient may commence to the next cycle [See Figure 1]. 
If neutrophils are less than 1 x 109/L and white blood count less than 3 x 109/L, filgrastim 
or lenograstim (GCSF) should be given for 2 days. 
 
However, if the blood count remains below the level required it should continue to be 
monitored at 48 hour intervals until it has reached the required level for proceeding with 
further treatment (platelets are greater than 75 x 109/L and rising, white count greater than 
3 x 109/L or the neutrophils are greater than 1 x 109/L). 
 
Please note that a delay of 14 days or more will require the patient to be withdrawn 
from study. 
 
If a patient is admitted with neutropenic sepsis, prophylactic antibiotics e.g. 
ciprofloxacin, day 10 – 21 (with or without filgrastim or lenograstim) should be used 
for all subsequent cycles.   
 
If the platelet nadir (day 13 -17) is less than 20 x 109/L, then a 20% dose reduction should 
be made on subsequent administration of carboplatin.    
 
Patients will be required to attend hospital to receive Carboplatin as a day case. 
 
 



 
Page 13 of 54 
Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
Day 1 of each 
cycle 
Blood check 
  
*Platelets >100 x109/L 
WBC >3 x109/L or 
#Neutrophils >1 
x109/L
Yes 
Study 
Treatment 
Recheck blood after 48 
hours 
 
*Platelets ≥ 75 x109/L 
 & rising 
WBC >3 x109/L or 
#Neutrophils >1 x109/L 
Yes 
No 
Study 
Treatment 
Continue to 
recheck blood 
every 48 hours. 
 
After 14 day delay 
patient off study 
No 
Yes 
Study 
Treatment 
No  
Recheck blood after 
48 hours 
 
*Platelets ≥ 75 x109/L 
 & rising  
WBC >3 x109/L or 
#Neutrophils >1 x109/L 
*If the patient has a nadir platelets count (day 13 -17) of 
< 20 x109/L the dose of carboplatin should be reduced 
by 20%.
#If the neutrophil count is < 1 x109/L and white blood 
count < 3 x109 /L then GCSF should be given for 2 days. 
Figure 1: Blood Count Guide Prior to Treatment 


 
 
 Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                 
    Page 14 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Treatment Flowchart  
 
Baseline PET-CT  
 
Contrast enhanced CT scan 
(Within 28 days of study entry) 
NB: If PET-CT was done instead of CT scan then the 
CT scan is not required if clinician already suspected 
diagnosis. 
Day 17-21 PET-CT scan 
(With low attenuation CT) 
Cycle 1 
Informed Consent 
Complete metabolic response 
on Day 17-21 PET-CT scan 
Further 2 cycles  
(3 in total) 
PET-CT scan 
(Within 28 days of 
end of treatment) 
Residual masses >3cm 
1 & 2 year post 
treatment contrast 
enhanced CT scan 
No 
Further 3 cycles  
(4 in total) 
Surgery 
Yes
Contrast enhanced CT scan  
2-3 months post-surgery & 
again at 2 years 
Yes 
Contrast enhanced CT 
scan at 2-3 months post 
end of treatment scan 
No 
Contrast enhanced CT 
scan 
(Within 28 days of end of 
treatment) 
Off Study 
Patient to receive 
conventional cisplatin 
therapy 
Partial Response 
Shown on Day 17-21 PET-
CT scan  


 
 
 
 Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                    Page 15 of 54 
 
3.3 
Study population 
 
The population for this study are patients diagnosed with metastatic seminoma with 
IGCCCG good prognosis disease. 
 
3.4  
Target accrual 
 
Up to 50 patients will be recruited into the study (assuming 5 patients may withdraw for 
reasons other than disease progression) over four years.  45 evaluable patients will be 
necessary to establish activity of Carboplatin AUC10 in this setting. 
4.0 
Eligibility, subject selection and withdrawal 
4.1 
Inclusion Criteria 
1. Metastatic seminoma-IGCCCG good prognosis. 
2. Glomerular filtration rate by EDTA clearance over 25 ml/min (a measured 
creatinine clearance using Cockcroft and Gault would be allowed if unable to 
perform EDTA clearance). 
3. ECOG Performance status 0-3. 
4. Normal Alpha-fetoprotein (All levels of Human chorionic gonadotropin and Lactate 
dehydrogenase are acceptable). 
5. Males aged ≥18 and ≤75 years. 
6. Able to give written informed consent prior to study entry. 
7. Patients must be sterile or agree to use adequate contraception during the period 
of therapy. 
4.2 
Exclusion Criteria 
1. 
Metastatic seminoma with any non-pulmonary visceral metastases. 
2. 
Raised Alpha-fetoprotein. 
3. 
Any previous chemotherapy or radiotherapy. 
4. 
Currently enrolled in any other investigational drug study. 
5. 
Other malignancy except basal cell. 
4.3 
Subject recruitment and screening 
 
Participants will be identified when attending clinic visits by a research nurse/investigator 
that will screen patients for entry into the study.  The possibility for study enrolment will be 
discussed and if appropriate, a patient information sheet will be provided by a member of 
the study team.  The patient details should be entered onto the pre-screening log (initials, 
date of birth, pre-screening date).  The patient should be given ample time to consider 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
entering the study.  If the patient refuses to enter into the study, the reason (if applicable) 
should be recorded on the pre-screening log (refer to section 5.2 for registration 
procedure). 
 
Patients from within the Anglian network will also be identified via a specialist testicular 
multidisciplinary team meeting which, is held fortnightly and attended by investigators and 
research nurses from different sites across the Anglian Network.   
 
4.4 
Withdrawal of subjects 
 
Patients will be informed that they have the right to withdraw from the study at any time, 
for any reason, without prejudice to their medical care.  The primary reason (if available) 
for a patient’s withdrawal from the study should be recorded on the case report form 
(CRF).  The right of patients to refuse to participate without giving reasons and prejudicing 
their further treatment will be respected.  Any patients who decide to withdraw their 
consent completely will have no further data collected.   However, if the patient withdraws 
from trial treatment only their data may be followed-up for survival as long as the patient 
is happy to do so. 
 
The investigator also has the right to withdraw patients from the study for any of the 
following reasons: 
 
 
Disease Progression. 
 
Occurrence of intolerable side effects. 
 
Non-compliance. 
 
A delay in treatment of 14 days or more. 
 
At the time of withdrawal, all end of study procedures should be completed (as per 
schedule of assessments).  The patient will remain in the study for the purposes of follow 
up and data analysis.             
 
4.4.1 Data collection and follow up for withdrawn subjects 
 
CRFs should be sent to the Centre for Experimental Cancer Medicine, Barts Cancer 
Institute within one month of patient completing each cycle. 
Subjects who are withdrawn are still evaluable for toxicity and efficacy if they have 
received at least one cycle of treatment and any data collected whilst receiving treatment 
will be used in the final analysis.  Patients who are withdrawn from the study will be 
followed up for 2 years after treatment.  Similarly, this follow up data will be used in the 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
final analysis.  Any patients who decide to withdraw their consent will have no further data 
collected unless they have given express permission to do so. 
 
5.0  
Study procedures and schedule of assessments 
5.1 
Informed consent procedures  
 
It is the responsibility of the Investigator, or a suitably trained doctor delegated by the 
Investigator to obtain written informed consent from each subject prior to participation in 
this study, following adequate explanation of the aims, methods, anticipated benefits and 
potential hazards of the study.  Ample time must be given for consideration by the patient 
before consenting to take part.  The Investigator or co-investigator (designee) must also 
fully explain to the subjects that they are not obliged to enter the study but, that they may 
choose to opt for standard treatment.  Alternatively, if they do wish to participate in the 
study they may withdraw at any time without giving a reason. 
 
If new safety information becomes available and significantly changes the risk/benefit of 
the study, the patient information sheet and consent form will be reviewed and updated 
immediately.  Patients who have been recruited into the study, including those already 
being treated, should be informed of the new information and given a copy of the revised 
information sheet and if necessary re-consent to continue in the study. 
5.2 
Registration/study procedures 
 
Following screening evaluation and patient consent, the study registration form should be 
completed and faxed to the Car-PET Clinical Trial Coordinator.  The patients initials, date 
of birth and date of consent will be recorded.  
CARPET TRIALS OFFICE 
REGISTRATION AND ENQUIRIES: 0207 882 8761 
FAX: 0207 882 8409 
EMAIL: bci-carpet@qmul.ac.uk 
(Office Hours 9-5pm) 
 
Each patient will be assigned a unique trial number after registration that should be used 
on ALL patient related documentation.  Once the form is received and the unique trial 
number has been generated, confirmation of this will be sent by fax.  
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
5.3 
Treatment procedures 
5.3.1 Pre-treatment investigations 
 
The following investigations must be completed before the patient can begin treatment: 
 
Physical examination. 
 
Contrast-enhanced staging CT scan of chest, abdomen & pelvis within 28 days of 
study entry.  NB: If clinician suspects patient to be eligible for trial they may only 
do the PET-CT scan as the CT element is sufficient for diagnosis.  The PET-CT 
scan will have to be done regardless of have a contrast-enhanced CT scan 
performed before study entry. 
 
Full body PET-CT within 28 days of study entry. 
 
Glomerular filtration rate by EDTA clearance (a measured creatinine clearance 
using Cockcroft and Gault would be allowed if unable to perform EDTA clearance). 
 
Alpha-fetoprotein, Human chorionic gonadotropin and Lactate dehydrogenase*. 
 
Hormone levels of Testosterone, Follicle-stimulating hormone (FSH) and 
Luteinizing hormone (LH). 
 
Full blood count. 
 
Urea electrolyte. 
 
Liver function tests. 
 
Please note that approximately 20mls (max) of blood will need to be taken at this time for future 
research.  Blood will be collected in three 7.5ml EDTA tubes containing anticoagulant.  The 
patient will need to sign a separate consent form agreeing for their samples to be used for 
future research.  Once consent has been obtained, the sample should be sent directly to The 
Orchid Tissue Bank lab using the post boxes to: 
Orchid Tissue Bank Manager 
Orchid Tissue Bank 
Centre for Experimental Cancer Medicine 
Barts Cancer Institute - a CR-UK Centre of Excellence 
Queen Mary University of London 
John Vane Science Centre 
Charterhouse Square 
LONDON EC1M 6BQ 
 
5.3.2 Investigations during and after treatment 
 
 
Physical examination on Day 1 (± 3 days) of cycle 2-4*. 
 
Full Blood Count, Urea electrolyte and Liver function tests on Day 1 (± 3 days) of 
cycle 2-4*. 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
Alpha-fetoprotein (AFP), Human chorionic gonadotropin (hCG) and Lactate 
dehydrogenase (LDH) on Day 1 during cycle 1-4, Day 13-17 of cycle 1-4 and Day 
17-21 of cycle 1. 
 
Full Blood Count repeated on Day 13-17 of cycle 1-4*. 
 
Hormone levels of Testosterone, Follicle-stimulating hormone (FSH) and 
Luteinizing hormone (LH) at end of treatment and annually thereafter during the 
follow up period of the trial. 
 
PET-CT scan on Day 17- 21 after the first cycle. 
 
PET-CT within 28 days of completing treatment (may be contrast enhanced CT if 
negative PET – CT scan on Day 17-21 of the first cycle). 
o If complete metabolic response is demonstrated contrast enhanced CT at 
1 year and 2 years post therapy. 
o If residual masses are present, a contrast enhanced CT should be 
performed at 2 months after the end of the treatment PET-CT scan and if 
the masses are greater than 3cm in diameter, surgery to remove them is 
recommended in accordance with current practices. 
 
If patients require surgery following their treatment, a contrast enhanced CT scan 
of the area must be performed 2-3 months after the surgery has taken place. 
 
If CR by chemo +/- surgery a final contrast enhanced CT at 2 years. 
 
Thereafter CT scan only if clinically indicated. 
 
* Patients who have a complete response to AUC-10 following cycle 1 will receive 2 further cycles.  
Those who do not achieve a complete response will have a further 3 cycles. 
 
5.3.3 Central review of PET-CT scans 
 
There are currently no well validated metabolic response criteria for PET-CT in seminoma.  
Hence, we will use the criteria for assessment of response developed for the evaluation 
of lymphoma [6]. 
 
A Complete Response will be defined as complete resolution of all previously seen sites 
of nodal and metastatic disease.  If residual sites of metastatic disease persist then the 
PET-CT will be used to evaluate metabolic activity.   
 
Metabolic Complete Remission will be defined as the level of FDG uptake within the lesion 
that is no greater than normal mediastinal uptake these patients will receive 3 cycles in 
total.  Lesions with uptake greater than the mediastinum will be viewed as non-complete 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
responders.  The PET data will be viewed on standardised SUV (standardised uptake 
value) setting of between 0 and 5.0 and a visual comparison will be made to assess the 
degree of uptake within abnormal tissue [7].  These criteria will have a high probability of 
distinguishing true complete responders from partial responders.  Contrast enhanced CTs 
will be evaluated via the standard response criteria (Appendix 4). 
 
All PET-CT scans will be centrally reviewed at University College London Hospital.  The 
results from the report will be used to determine the number of further treatment cycle’s 
patients will require, following cycle 1.  Copies of locally reported scans (where relevant) 
should be sent to the central reviewer via the secure NHS Image Exchange Portal system 
(IEP) for review by the central reviewer (please refer to appendix 7).   Sending images via 
IEP will not apply to sites where patients are scanned at UCLH, however, sites must 
ensure that the proforma is completed and sent to remind the central reviewer.  In addition 
to sending images via the secure IEP system, sites must email a copy of the Proforma 
Request form (see Appendix 5 and 6) that is appropriate to each site) to the central 
reviewer to indicate that an image has been sent via IEP. 
 
The central reviewer will review the image and return the generated report within the 
appropriate timelines as stated in the table below (see Appendix 7); 
 
All scans for central review to be sent to;; 
Dr Rizwan Syed 
Consultant in Nuclear Medicine 
Institute of Nuclear Medicine, T5 
University College Hospital  
235 Euston Road,  
LONDON NW1 2BU  
Fax:  0203 447 0591 
Proforma Request form to be emailed to:  
rizwansyed@nhs.net and 
   
 
 
shane.blanchflower@nhs.net  
 
The central review reporting of the Baseline and Day 17-21 PET-CTs will take place within 
3 weeks of the site either sending image or the patient having their scan done at UCLH.  
The PET-CT scans must be received within this timeframe in order for the patient’s 
response to treatment to be assessed and the decision on whether the patient 
receives 3 or 4 cycles can be made. 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
Low dose attenuation correction CT will be performed at the time of the PET acquisition. 
Follow up conventional diagnostic CT scans from this point on should be received within 
two months of being performed. 
 
 
If reports have not been received by the site within the timelines as detailed above, please 
follow the escalation process as detailed in Appendix 7. 
Scan 
Report to be received within 
Baseline PET-CT & Baseline contrast enhanced CT 
Within 3 wks of sending image/the 
PET scan (if done at UCLH) 
Day 17-21 
Within 3 wks of sending image/the 
PET scan (if done at UCLH) 
Contrast enhanced CT performed post cycle 2 (if applicable) 
Within 3 wks of sending image/the 
PET scan (if done at UCLH) 
End of Treatment PET-CT or contrast enhanced CT 
2 months 
All other Contrast enhanced CTs as per follow up 
2 months 


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     
 Page 22 of 54 
 
5.4 
Study Flowchart 
 
 
*see appendix 3 for definitions 
 
1. 
Glomerular filtration rate by EDTA clearance (a measured creatinine clearance using Cockcroft and Gault would be allowed if unable to perform EDTA clearance 
in adequate timeframe). 
2  
Within 28 days of beginning study treatment.  NB: If clinical decision was made a PET-CT scan can replace a CT scan at baseline (refer to section 5.3.1). 
3  
To be performed up to 1 week after day 21 of cycle. 
4. 
Patients who have a complete response to AUC-10 following cycle 1 will receive 2 further cycles. Those who do not achieve a complete response will have a 
further 3 cycles*. 
5. 
To be performed with 28 days of completing treatment.  May be contrast enhanced CT if negative PET-CT scan on Day 17-21 of cycle 1. 
6  
Follow up to be carried out 2 monthly for 1st year and 4 monthly for 2nd year.  
 
 
 
PRE-TREATMENT  
VISIT 
CYCLE 1 * 
DAY 17-21 
CYCLE 1-4 
DAY 13-178 
CYCLE 2-44 
DAY 19 
END OF 
TREATMENT 
FOLLOW UP6 
Informed Consent 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
ECOG Performance 
Status 
 
 
 
 
 
 
Physical Exam & 
Vital Signs 
 
 
 
 
 
 
PET-CT Scan 
2 
3 
 
 
5 
 
Contrast Enhanced 
CT – Chest, Abdo, Pelvis 
2 
 
 
 
 
 
 
7 
Blood Sample – 
Future Research 
10 
 
 
 
 
 
GFR1 
 
 
 
 
 
 
Full Blood Count 
 
 
 
 
 
 
U&E’s And LFT’s 
 
 
 
 
 
 
AFP, hCG & LDH 
 
 
 
 
 
 
Testosterone, FSH and LH 
 
 
 
 
 
11 
AE Reporting 
 
To be reported from the start of the first treatment and within 30 days after the 
administration of the last dose of study drug 
Concomitant Medication 
 
To be reported from the start of the first treatment and within 30 days after the 
administration of the last dose of study drug 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
7  
CT scan to be performed in all patients who have a complete response to treatment (+/- surgery) at one and two year post therapy. For those patients requiring 
surgery following their treatment, a repeat CT scan must be carried out 2 months post end of treatment PET-CT scan and again at 2-3 months after the surgery 
has taken place (PET is not required for follow-up scans)*.8. 
Full blood count repeated to determine possible dose reductions also performed on Day 13-17. 
9. 
± 3 day allowable window 
10. 
Patients who have given consent for the storage of their samples (separate consent from the trial – will be indicated on registration form). 
11. 
The hormone tests should be performed at baseline, end of treatment and annually at follow ups. 
 
 


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     Page 24 of 54 
 
5.5 
Follow up  
 
 
Patients will be followed up as part of the study for 2 years following completion 
of treatment. 
 
Outpatient follow up visits will be carried out 2 monthly in the first year and 4 
monthly in the second year. Patients will then be followed at the PI’s discretion 
and/or standard care. 
 
Details of disease progression must be documented on the CRF. 
 
Any further therapy for metastatic seminoma must be documented on the CRF. 
 
6.0 
Investigational Medicinal Product(s)/treatment details 
6.1 
Description of IMP 
 
Carboplatin is a platinum-containing anticancer agent much like cisplatin but is more toxic 
to the myeloid elements of bone marrow.  However when used as a chemotherapy agent 
in solid tumours it produces less nausea, neurotoxicity, ototoxicity, and nephrotoxicity. 
6.2 
Product sourcing manufacture and supply 
 
Carboplatin is a licensed product within the EU.  Local pharmacies will source carboplatin 
from NHS commercial stock.   
6.3 
Pre-Medication 
 
In the administration of prophylactic anti-emetics in conjunction with highly emetogenic 
chemotherapy (e.g. dexamethasone 16mg and a 5-HT3 antagonist pre carboplatin, 
dexamethasone 8mg/day for days 2 and 3 and metoclopramide 20mg 3x/day for days 1 
to 5) centres should follow local practice. 
6.4 
Prescription of IMP 
 
Prescriptions for carboplatin for this study should be in accordance with local policies and 
should be identifiable as being part of the clinical trial.  The local PI or doctor on the 
delegation log will only be able to prescribe carboplatin. 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
6.5 
Preparation and administration of IMP 
 
Carboplatin will be prepared by chemotherapy pharmacy departments and the dose 
calculated using the Calvert formula, as below: 
 
Dose (mg) = (GFR + 25) x10 
 
Unless dictated by haematological toxicity, the Carboplatin dose should not be 
recalculated for each cycle.  However, if the serum Creatinine has risen by > 20% above 
baseline, the Carboplatin dose must be recalculated using the Calvert formula with GFR 
determined by EDTA clearance.  At the discretion of the PI an estimated creatinine 
clearance can be calculated using e.g. Cockcroft and Gault (or as per local policy) if the 
site is unable to obtain EDTA clearance. 
 
This dose should be administered in 500ml glucose 5% over 60 minutes, or as per 
institutional local practice. 
Dose banding is not permitted; however, rounding of carboplatin dose to nearest 10 mg is 
acceptable. 
 
6.6 
Prior and concomitant therapies 
 
Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, 
vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity due to 
carboplatin induced changes in renal clearance. 
 
Combination therapy with other myelosuppressive agents may require dose changes or 
rescheduling of doses in order to minimise the additive myelosuppressive effects. 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
6.6.1 Recording concomitant medications 
 
Concomitant medications should be reported from the start of the first treatment and within 
30 days after the administration of the last dose of study drug.  As the IMP (Carboplatin) 
is a licensed product, there is no requirement to record concomitant medications 
administered as supportive care in the CRFs i.e. all anti-emetics, medications for 
indigestion, acid suppression, routine antibiotics for infection/ neutropenia and simple 
analgesics.  However, concomitant medications are expected to be fully listed on all 
Serious Adverse Event forms should a safety event occur and reported to the sponsor 
within the appropriate timelines. 
 
The concomitant medications which are not required to be reported on CRFs are listed on 
the next page. 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
Fluids 
0.9% NaCl 
5% Glucose 
Compound Sodium Lactate (Hartman’s Solution) 
 
With or without additives e.g. KCl, MgSO4, Calcium 
 
Anti-emetics 
Domperidone 
Metoclopramide 
Cyclizine 
Levomepromazine 
Olanzapine 
Haloperidol 
Lorazepam 
 
Granisetron 
Ondansetron 
 
Aprepitant 
 
Dexamethasone 
Prednisolone 
 
Analgesics 
Aspirin 
Paracetamol 
Codeine 
Dihydrocodeine 
Tramadol 
 
Morphine 
Diamorphine 
Oxycodone 
Fentanyl 
 
Naproxen 
Ibuprofen 
Diclofenac 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics 
Co-amoxiclav 
Piperacillin/ Tazobactam 
Amoxicillin 
Benzylpenicillin 
Flucloxacillin 
 
Cefuroxime 
Ceftriaxone 
Ceftazidime 
 
Meropenem 
Imipenem 
 
Gentamicin 
Amikacin 
Vancomycin 
Teicoplanin 
 
Co-trimoxazole 
Doxycycline 
Tigecycline 
 
Trimethoprim 
 
Ciprofloxicin 
Levofloxacin 
 
Clarithromycin 
 
Itraconazole 
Fluconazole 
Caspofungin 
Amphotericin 
Micafungin 
Terbinafine 
 
Aciclovir 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
List of concomitant medications not required to be reported 
 
 
 
Acid Suppression 
Ranitidine 
Omeprazole 
Pantoprazole 
Lansoprazole 
 
Gaviscon 
 
Caphosol 
 
Anti-asthmatics 
Salbutamol 
Terbutaline 
Beclometasone 
Budesonide 
Formoterol 
 
 
 
 
 
Diuretics 
Bumetanide 
Furosemide 
Spironolactone 
Bendroflumethiazide 
 
 
Statins 
Simvastatin 
Pravastatin 
Atorvastatin 
 
Anti-hypertensives 
Atenolol 
Bisoprolol 
Metoprolol 
Ramipril 
Perindopril 
 
Lisinopril 
Enalapril 
Losartan 
Candasaratan 
Irbesartan 
Valsartan 
Lercanidipine 
Amlodipine 
Lacidipine 
Nifedioine 
Indapamide 
 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
6.7 
Dose modification/reduction/delay 
 
If the patient has a nadir platelet count of <20 x109 /L then the dose of carboplatin should 
be reduced by 20%. 
 
Please refer to figure 1 for guidance regarding dose delays. 
6.8  
Toxicity profiles 
 
Please refer to the current SmPC toxicity and side effects information for carboplatin.  
6.9 
Labelling/Packaging 
 
Labelling of the IMP will be undertaken by pharmacy staff, and will contain information to 
meet the applicable regulatory requirements of Annex 13. 
6.10 
Blinding of IMP 
 
N/A 
6.11 
Receipt of IMP supplies/Storage 
 
Carboplatin supplies will be sourced from NHS commercial stock therefore sites will be 
responsible for the ordering, receipt and storage of carboplatin.  Storage will be in 
accordance with the current SmPC for carboplatin. 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
7.0 
Pharmacovigilance 
7.1 
General definitions 
7.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject who has been administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporarily associated with the use of a medicinal (investigational or marketed) 
product, whether or not considered related to the medicinal product. 
7.1.2 Adverse Reaction (AR) 
 
An adverse reaction is any untoward or unintended response in a subject to an 
Investigational Medicinal Product (IMP), which is related to any dose administered to that 
subject.  All adverse events judged by either the reporting investigator or the sponsor as 
having a reasonable causal relationship to a medicinal product qualify as adverse 
reactions.  The expression reasonable causal relationship means to convey in general that 
there is evidence or argument to suggest a causal relationship.  
7.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
 
A serious adverse event or reaction is any untoward medical occurrence at any dose that: 
 
Results in death 
 
Is life-threatening (defined as an event in which the patient or subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe) 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is an important medical event (defined as a medical event[s] that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardize 
the patient/subject or may require intervention (e.g., medical, surgical) to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalisation. 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
There is a distinction between the intensity (mild, moderate, or severe) and the 
seriousness of an adverse event.  Thus, a severe reaction is not necessarily a SAE.  For 
example, a headache may be severe in intensity, but would not be serious unless it met 
one of the previously listed criteria for SAEs. 
7.1.4 Suspected Unexpected Serious Adverse Events - SUSAR’s  
 
A SUSAR is any suspected unexpected adverse reaction related (or possibly related) to 
an IMP that is both unexpected and serious.  In this case the event is not outlined in the 
Reference Safety Information (RSI) contained within the Summary of Product 
Characteristics (SmPC) for Carboplatin (section 4.8 of SmPC) 
 
7.2 Investigators Assessment 
 
It is the Chief/Principal Investigator’s responsibility to assess and report all adverse events 
or reactions occurring from the time of patient registration until events that occur 30 days 
following the last dose of study medication or are thought to be related to study drug. 
 
Seriousness 
 
 
Results in death 
 
Is life-threatening (defined as an event in which the patient or subject was at risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe) 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is an important medical event (defined as a medical event[s] that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardize 
the patient/subject or may require intervention (e.g., medical, surgical) to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalisation. 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
Causality 
 
The relationship or association of the study medication in causing or contributing to the 
AE will be characterized as either none, unlikely, possible or probable. 
 
Expectedness 
 
 
Expected 
 
Unexpected 
 
Severity 
NCI 
CTCAE 
v4.0 
criteria 
should 
be 
applied 
for 
assessing/reporting 
event 
severity/intensity: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
7.3 Notification and reporting adverse events or reactions 
 
Patients will be monitored and questioned at every visit whilst on study treatment regarding 
the occurrence and nature of any adverse experiences.  Any AE, including either observed 
or volunteered problems, complaints, or symptoms (whether or not associated with study 
medication) that begin at any time between the start of the first treatment and within 30 
days after the administration of the last dose of study drug are to be recorded in the 
relevant section of the relevant CRF and sent to the CarPET Trials office within one month 
of the form being due.   
7.4 
Notification and reporting of serious adverse events/SUSAR 
 
All AEs that are serious, unexpected, and definitely, probably, or possibly related to the 
study drug that occur during treatment or within 28 days of stopping treatment must be 
reported on the ‘Serious Adverse Event Form’ to the CarPET Trials Coordinator within 24 
hours of the Investigator/Sub-Investigator becoming aware of the event.  
 
The SAE form must be signed off by the Principal Investigator (or medically 
qualified delegate) at the participating site and faxed or emailed to the Car-PET 
Coordinator on 0207 882 8409 or bci-carpet@qmul.ac.uk together with relevant 
accompanying anonymised copies of treatment investigations.   
 
It will then be the responsibility of the Chief Investigator to inform the sponsor within 24 
hours of becoming aware of the SAE.  The relationship or association of the study 
medication in causing or contributing to the AE will be characterized as definitely, probably, 
possibly, or not related, as defined in Section 7.1. 
 
7.5 
Notification and reporting of serious adverse events/SUSAR 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
In accordance to The Medicines for Human Use (Clinical Trials) Regulation 2004 and its 
amendments, the prompt reporting of SUSAR’s to relevant authorities lies with the 
sponsor.  However, any SUSAR’s which occur at any participating site should be reported 
to the Chief Investigator within 24 hours of the participating site learning of the event.  It is 
the CI’s responsibility to then report these to the sponsor.  The sponsor will then submit 
these reports to the Competent Authority of the member state within 7 days of receipt for 
fatal or life threatening SUSARs or within 15 days for all other SUSARs. 
 
Follow-up information by the sponsor will be sought within 8 days.  Each report should 
contain concise and clear information regarding the SUSAR. 
 
7.6 
Expected SAEs/SARs 
 
 
Febrile neutropenia (requiring hospital admission) 
 
Neutropenia Grade 0-4 (asymptomatic) 
 
Mucositis Grade 0-4 (requiring hospital admission) 
 
Diarrhoea Grade 0-4 (requiring hospital admission) 
 
Thrombocytopenia Grade 0-4 
 
Renal Impairment (not requiring dialysis) 
 
Nausea and vomiting Grade 0-4 (requiring hospital admission) 
 
Neuropathy Grade 0-3 
 
Abnormal LFTs/Jaundice (resolving within 14 days of treatment) 
 
As the IMP used in this study is licensed in the UK the expected SAE/SAR’s are outlined 
in the current SmPC under undesirable effects and the expected SAE/SARs listed 
above should be recorded in the medical notes as well as the relevant CRF and sent to 
the CarPET Trials Office within one month of the form being due.  No SAE forms regarding 
these expected SAE/SARs should be completed and sent to the sponsor. 
7.7 
Pregnancy 
 
Patients must use adequate contraception whilst on the study and for at least 6 months 
after they stop receiving treatment as the adverse effects on reproduction are unknown. 
If a patient’s partner becomes pregnant whilst enrolled in this CTIMP in which the foetus 
has been exposed to an investigational medicinal product, immediate reporting to the 
sponsor is required (within one working day of the PI/CI becoming aware of the event) 


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using a JRMO pregnancy template form.  The CI/PI has the responsibility to ensure that 
the pregnancy form is completed and sent to the sponsor within the agreed timelines.  
Please state whether the patient can continue on the study or whether the patient has to 
be prematurely withdrawn from the study here. 
 
The PI/CI also must follow up the pregnancy until delivery as well as monitoring the 
development of the newborn until birth.  Any events that occur during this time that could 
be considered to be a SAE must be reported to the sponsor in line with section 7.6 utilising 
the sponsor SAE reporting form.  Pregnant partners of participants will be asked to give 
consent for the release of this information to the study team. 
7.8 Urgent Safety Measures 
 
The CI may take urgent safety measures to ensure the safety and protection of the clinical 
trial subjects from any immediate hazard to their health and safety, this is defined in 
Regulation 30 of the Medicines for Human Use (Clinical Trials) Regulations 2004 
[Statutory Instrument 2004/1031], as amended by Statutory Instrument 2006/1928.  The 
measures should be taken immediately. In this instance, the approval of the Licensing 
Authority Approval prior to implementing these safety measures is not required. However, 
it is the responsibility of the CI to inform the sponsor, Main Research Ethics Committee 
(via telephone) and the MHRA (via telephone for discussion with the medical assessor at 
the clinical trials unit) of this event immediately.  
 
The CI has an obligation to inform both the MHRA and Main Ethics Committee in writing 
within 3 days, in the form of a substantial amendment. The sponsor (JRMO) must be sent 
a copy of the correspondence with regards to this matter. 
 
 


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8 
Annual Reports  
8.1 
Development Safety update reports (DSURs) and Annual Progress Reports 
(APRs) 
 
The CI will submit APRs to the main REC and the sponsor on the anniversary date of 
obtaining a Favourable Opinion from the main REC using the National Research Ethics 
Service (NRES) template. 
 
A DSUR will be submitted by the CI to the Sponsor, the relevant Ethics Committee and 
MHRA on the anniversary date of the “Notice of Acceptance’ letter from the MHRA using 
the DSUR template provided by the sponsor. Subsequent DSUR reports will be due within 
60 days of the anniversary date. The CI will carry out a risk benefit analysis of the IMPs 
encompassing all events having arisen on the trial. 
9 
Data handling and record keeping 
9.1 
Confidentiality 
 
All information which is generated in the study will be kept strictly confidential.  The 
researchers conducting the study will abide by the Data Protection Act 1998, and the rights 
the patient has under this act.   
 
Once the patient consents to participate in the study their GP will be informed.  Parts of  
the patients medical records and the data collected for the study will be reviewed by 
authorised personnel from Queen Mary University of London and also Bart’s & The 
London NHS Trust who are the sponsors of this study.  It may also be reviewed by 
representatives of regulatory authorities and other authorised personnel from the patient’s 
trust, to check that the study is being carried out correctly.  This is clearly stated on the 
consent form.  
 
All of the above bodies have a duty of confidentiality to the patient as a research participant 
and nothing that could reveal their identity will be disclosed outside the research site.  All 
data will be stored in a locked and dedicated data room only accessed by authorised 
personnel. 
9.2 
Essential Study documents 
 
All study related documents should be filed in the investigator’s study site file.  It should 
contain the protocol/amendments, Case Report and Query forms, Regulatory approvals 
with correspondence, sample patient information sheet and informed consent form, drug 


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records, 
staff 
curriculum 
vitae 
and 
delegation 
logs 
and 
other 
appropriate 
documents/correspondence.  The coordinating centre will inform the PI of any regulatory 
updates and forward on any relevant documentation.  It is the participating sites 
responsibility to maintain this file and keep all staff records, including delegation logs up 
to date. 
9.3 
Case Report Forms 
 
The Case Report Form (CRF) must be completed legibly in black ink.  Subjects are to be 
identified by initials, birth date, and subject number, if applicable.  All requested information 
must be entered on the CRF in the spaces provided.  If an item is not applicable it should 
be documented as such; do not leave a black space.  The completed CRF must be 
promptly reviewed, signed and dated by the Investigator or Sub-Investigator where 
applicable. 
 
Any change or correction to a CRF should be made by striking through the incorrect entry 
with a single line (not obscuring the original entry) and then entering the correct information 
adjacent to the incorrect entry.  The correction must be initialled and dated by the person 
making the corrections.   
9.4 
Record retention and archiving 
 
At the end of the trial, all essential documents as defined by ICH GCP (including CRFs, 
source documents, consent forms, laboratory results) will be securely archived by the 
coordinating and participating centres for a minimum of 20 years. During this time, 
documents must remain available for inspection by the Sponsor, auditors and members 
from regulatory bodies and the CI must be informed of the location of the archived material 
and the retrieval process.  Following written authorisation from the Sponsor, arrangements 
for confidential destruction will then be made.   
9.5 
Compliance  
 
This study will be conducted in accordance with the principles of ICH Good Clinical 
Practice (GCP) as laid out in The Medicines for Human Use (Clinical Trials) Regulation 
2004 and its amendments. 
 
In addition, internal auditors and Competent Authority personnel will be allowed access to 
CRFs, source documents and other study files to evaluate the study.  Audit reports will be 
kept confidential. 


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10 
Governance Issues 
10.1 
Risk Assessment 
 
The sponsor together with the CI have assessed this study according to their risk 
assessment SOP 28. 
10.2  Summary Monitoring Plan  
 
On-Site monitoring will be performed on this trial.  The trial coordinator/monitor should 
perform the first monitoring visit within 1 month of the first patient being enrolled at a site.  
Monitoring visits will be performed a minimum of twice a year during the recruitment and 
treatment period. 
 
Sites that do not recruit any patients into a study will undergo on-site monitoring once a 
year. 
 
The frequency of visits may change (increase or decrease) depending on the issues raised 
during the trial (death, SAE, audit or inspections, site not recruiting).  Any decrease in 
monitoring at a site will be approved by a member of the CECM Management Team and 
the Sponsor. 
 
Source Data Verification 
 
100 % SDV will be performed on informed consent. 
100 % SDV will be performed on inclusion / exclusion criteria. 
 
The following data points will undergo SDV for all patients 
 
Adverse events and toxicities levels; 
 
Metabolic response rate by FDG PET-CT scan and number of cycles required; 
 
Follow Up survival dates and progression disease dates for Progression Free 
Survival and Overall Survival. 
 
100% SDV on all data points will be performed for a minimum of one patient per site or 
approximately 5% of all patients, whichever is greater. 
 
Reasons for not performing on-site monitoring must be agreed with the CECM 
Management Team and the Sponsor and be fully documented in the TMF. 


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Original CRFs will be sent by post from site to the trial coordinator/monitor in a timely 
manner.  Upon receipt of CRFs the trial coordinator/monitor will review for any obvious 
errors and data queries will be raised. 
 
The following central facilities are utilised in this study:- 
 
• Orchid tissue bank: Queen Mary University of London, Molecular Oncology Unit, John 
Vane Science Centre, Charterhouse Square, London, EC1M 6BQ. 
• Central review of scans: University College London Hospital. 
 
The following facility will undergo yearly monitoring visits for the duration of their 
participation in the study during the recruitment and treatment phase – once the follow-up 
phase is entered, its involvement with the trial will end. As such, monitoring will cease and 
the facility will be subject to a close-out visit: 
• 
Orchid tissue bank. 
 
The following facility will undergo 6 monthly monitoring visits for the duration of their 
participation in the study during the recruitment and treatment phase – once the follow-up 
phase is entered, its involvement with the trial will end. As such, monitoring will cease and 
the facility will be subject to a close-out visit: 
•  
University College London Hospital - Institute of Nuclear Medicine 
 
A summary of all monitoring activity for this study will be provided to the Sponsor at least 
every 6 months. 
10.3 
Audit and Inspection 
 
This study may be audited by representatives from the coordinating centre and sponsor.  
The investigator and institution will be informed of the audit outcome.  Investigators are 
obliged to cooperate in any audit allowing the auditor direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor to discuss 
any findings or issues.  Audit may occur at any time during or after completion of the study. 
 
In addition, inspections may also be carried out by the Competent Authority at any time 
and the investigator should notify the sponsor immediately if there are any such plans for 
an inspection. 
 
10.4 
Serious breaches in GCP or study protocol 
 


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All investigators participating in the study will promptly notify the Chief Investigator or 
Sponsor of a serious breach as soon as they become aware.  This is defined in Regulation 
29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 [Statutory 
Instrument 2004/1031], as amended by Statutory Instrument 2006/1928 and contains the 
requirements for notifying serious breaches of GCP or study protocol.  The CI is then 
responsible for notifying the Sponsor within 1 working day of becoming aware of a serious 
breach. 
 
The sponsor (JRMO) is responsible for notifying the licensing authority in writing of any 
serious breach of: 
(a) The conditions and principles of GCP in connection with that trial; or 
(b) The protocol relating to that trial, as amended from time to time in accordance with 
regulations 22 to 25, within 7 days of becoming aware of that breach. 
 
A “serious breach” is a breach which is likely to affect to a significant degree:- 
The safety or physical or mental integrity of the subjects of the trial; or the scientific value 
of the trial. 
 
Participating centres should contact the coordinating centre or CI for further information. 
10.5 
Quality Assurance 
 
This study will be conducted in accordance with the Centre of Experimental Cancer 
Medicine standard operating procedures and those of the sponsor.  
10.6 
Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  An independent Ethics committee (IEC) will review all appropriate 
study documentation in order to safeguard the rights, safety and wellbeing of patients.  
The study will only be conducted at sites where appropriate approval has been obtained. 
 
The study coordinating team will inform the IEC of any changes to the conduct of the study 
and seek approval for these changes and any amended patient materials.  The Chief 
investigator will maintain an accurate and complete record of all written correspondence 
to and from the IEC and will agree to share all such documents and reports with the 
sponsor. 
 


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The informed consent and any other documentation provided to subjects will be revised if 
important new information becomes available that is relevant to the subject’s consent. 
Amended documents will be approved by the IEC before distribution to patients. 
10.7 
Trial Committees 
10.7.1 Trial Steering Committee (TSC) 
A Trial Steering Committee will be convened and will provide an internal review of the 
conduct of this clinical trial to ensure continuing patient safety as well as the validity and 
scientific merit of the trial. 
 
Details of the Trial Steering Committee will be described in the TSC remit and will be 
updated if any change occurs during the course of the study. The TSC remit will be 
provided to all members. Details of the frequency of the meetings and the information held 
will be described in the TSC remit. 
 
10.7.2 Trial Management Group (TMG) 
 
Details of the trial management committee will be described in the TMG remit and will be 
updated if any change occurs during the course of the study. The TMG remit will be 
provided to all members.  
 
The Trial Management Group will consist of, as a minimum, the Chief Investigator, 
Statistician, and Trial Co-ordination staff. They will be responsible for the day-to-day 
running and management of the trial. The frequency of the meetings and the information 
held will be described in the TMG remit. 
 
 


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11 
Statistics 
11.1 Endpoints 
11.1.1 Primary Endpoints 
 
2-year Progression free survival 
 
11.1.2 Secondary Endpoints 
 
Metabolic response 
     Overall survival 
     Toxicity level (CTCAE version 4.03) 
 
11.1.3 Definition of end of study 
 
Patients will be recruited for 48 months. Patients will be followed up as part of the study 
for 2 years following completion of treatment.  The end of the study will be 3 months after 
the date when the last patient has completed his final follow up visit. 
11.2 
Statistical considerations 
11.2.1 Sample Size 
 
The primary objective is to gain a preliminary indication on whether carboplatin AUC-10 is 
worthwhile considering in a phase III study, using the progression free survival (PFS) rate 
as a criterion. A’Hern’s single-stage procedure is used to estimate the number of patients 
required [8].  
 
The primary outcome is the percentage of patients progression-free at 2-years. Therefore, 
all patients must have at least 2-years follow-up (unless they have died or their disease 
has progressed). An MRC study [1] showed that PFS rate at 3 years in standard 
chemotherapy, BEP, is 81%. It is also known that PFS rate at 2-years and 3-years are the 
same [2]. Carboplatin AUC-10 should not therefore have a 2-year PFS rate of 75% or less, 
and it would only be worth considering in a phase III study if the true rate were 90% or 
more. This information is used in A’Hern’s single stage design to yield a sample size of 45 
patients, with 80% power and one-sided test of significance at the 5% level. Here the 
statistical assumption of this design is that there is 80% chance of concluding that 
Carboplatin AUC-10 is effective if the true response rate is 90% or more, but only a 5% 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
chance of concluding it is effective if the response rate is 75% or less. To allow for a 10% 
drop-out rate the intention is to recruit 50 patients. 
11.2.2  Planned recruitment rate 
 
It is planned to have the study performed at approximately 4 centres to recruit around 10-
12 patients per year. Assuming 5 patients may withdraw from the study for reasons other 
than disease progression/intolerable side effects, up to 50 patients may be entered in total.  
In the event that the first centres initiated are not able to recruit sufficient patients, further 
centres may be recruited. Total duration of study recruitment is approximately 4 years.  
 
11.3 
Statistical Analysis 
 
All analyses in this study are descriptive and exploratory by nature. Results will be 
summarised with descriptive statistics (i.e. sample size, mean, and standard deviation, 
minimum, maximum and median for continuous variables and with tabulations/frequency 
tables/case listings for categorical variables).  Incidence of adverse events will be 
tabulated. Laboratory data will also be analysed and summarised.  
 
Two analysis sets will be defined: 
 
The Full Analysis Set (FAS) will consist of all patients who completed at least one 
cycle of Carboplatin AUC-10 and for whom relevant data is available at baseline 
and follow up. 
 
The Safety analysis set (SS) will consist of all patients who received at least one 
dose of Carboplatin AUC-10.  
 
The FAS will be used for all activity summaries; the SS will be used for all safety 
summaries. Further descriptions of the statistical analyses will be given in the Study 
Statistical Analysis Plan, to be finalised prior to database lock. 
 
11.4 
Frequency of analysis 
 
The data will be analysed at the end of the study.  There will be no interim analysis. 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
11.5 
Primary endpoint analysis 
 
The primary efficacy endpoint is Progression Free Survival (PFS) rate at 2 years.  Patients 
who do not complete 2 years follow-up for reasons other than death will be censored at 
the last date of follow-up.  The PFS rate will be determined for the Carboplatin AUC-10, 
along with a 95% confidence interval, and the Kaplan-Meier curves will be plotted. The 
study result will be considered positive if the PFS rate for patients on Carboplatin AUC-10 
is consistent with a true difference of 15% or more from standard chemo i.e. if there are at 
least 39 PFS patients out of the first 45 patients at 2 years.  
 
11.6 
Secondary endpoint analysis 
 
Subgroup analyses of the PFS rate will be performed in terms of patients with complete 
or partial response at 2 years. 
 
The analysis of safety will include all patients who received at least one cycle of treatment.  
Safety and tolerability of Carboplatin AUC-10 will be assessed in terms of changes in 
laboratory parameters, vital signs, the incidence and severity of Adverse Events, and of 
toxicities according to the CTCAE classification (version 4.03). 
 
The proportion of patients at each toxicity grade (0 to 4) of any type (including vomiting, 
nausea and diarrhoea) will be summarised. Safety analysis will be performed based on 
safety data set.  
 
Metabolic response rate will be assessed as described in section 5.3.3.   
 
11.7 
Interim analysis 
 
No interim analyses are planned as the Carboplatin AUC-10 is considered to be relatively 
safer than the standard chemotherapy. 
 
12 
Sponsorship and Indemnity 
 
Barts Health NHS Trust is the sponsor and will be providing indemnity for this study. 
 
13 
Publication policy 
 
This is an investigator-led study sponsored by the CI’s substantive employer, Barts Health 
NHS Trust.  The data collected will not be used to licence/register any pharmaceuticals.  


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Authorship of the final manuscript(s), interim publications, or abstracts will be decided 
according to active participation in the statistical design, Trial Steering Committee, accrual 
of eligible patients and statistical analysis.   
 
Contributing centres (and participating investigators) will be acknowledged in the final 
manuscript, and the correct designation for this site is ‘Centre for Experimental Cancer 
Medicine, Barts Cancer Institute, Queen Mary University of London’.  Representative for 
the sponsor will be added, as appropriate, as co-authors.   No participant may present 
data from his/her centre separately from the rest of the study results unless approved by 
the Trial Steering Committee and the sponsor.  
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
 
14 
References 
 
1. Horwich A, Oliver RT, Wilkinson PM, et al.: A medical research council randomized trial 
of single agent carboplatin versus etoposide and cisplatin for advanced metastatic 
seminoma. MRC Testicular Tumour Working Party.  British Journal of Cancer 2000; 
83(12): 1623-9. 
2. Bokemeyer C, Kollmannsberger C, Stenning SP, et al.: Metastatic seminoma treated 
with either single agent carboplatin or cisplatin-based combination chemotherapy: a 
pooled analysis of two randomised trials. Br J Cancer 2004; 91(4): 683-687. 
3. Shamash J, McLaren B, LeVay JH, et al.: Carboplatin AUC8 in combination with 
etoposide and bleomycin in the treatment of intermediate and poor-risk metastatic germ 
cell tumours: a phase II study.  Cancer Chemotherapy & Pharmacology 2001; 47(4): 370-
2. 
4. Horwich A, Sleijfer DT, Fossa SD, et al.: Randomized trial of bleomycin, etoposide, and 
cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis 
metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research 
Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 
1997; 15(5): 1844-52. 
5. Gore M, Mainwaring P, A'Hern R, et al.: Randomized trial of dose-intensity with single-
agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological 
Oncology Group. J Clin Oncol 1998; 16(7): 2426-34. 
6. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007; 25(5): 579-86. 
7. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography 
for response assessment of lymphoma: consensus of the Imaging Subcommittee of 
International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25(5): 571-8. 
8. A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 2001; 
20(6): 859-66. 
9. Oken MM, Creech RH, Tormey DC, et al.: Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6): 649-55. 
10. Moskowitz CH: Interim PET-CT in the management of diffuse large B-cell lymphoma. 
ASH Education Book, 2012; 8(1): 397-401. 
 


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15 
Appendices 
 
APPENDIX 1 – ECOG PERFORMANCE STATUS 
 
 
* As published in American Journal of Clinical Oncology [9] 
 
 
ECOG* 
STATUS 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     
 Page 47 of 54 
 
APPENDIX 2 – PET-CT RESPONSE DEFINITIONS FOR CLINICAL TRIALS* 
 
 
 
 
 
RESPONSE 
DEFINITION 
NODAL MASSES 
 
 
CR 
 
 
 
Disappearance of all evidence 
of disease 
 
a. FDG-avid or PET positive prior to therapy; 
mass of any size permitted if PET negative 
b. Variably FDG-avid or PET negative; 
regression to normal size on CT 
 
 
 
 
PR 
 
 
 
 
Regression of measurable 
disease and no new sites 
 
>50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of 
other nodes 
a. FDG-avid or PET positive prior to therapy; 
one or more PET positive at previously 
involved site 
b. Variably FDG-avid or PET negative; 
regression on CT  
 
 
 
SD 
 
 
 
Failure to attain CR/PR or PD 
 
a. FDG-avid or PET positive prior to therapy; 
PET positive at prior sites of disease and no 
new sites on CT or PET 
b. Variably FDG-avid or PET negative; no 
change in size of previous lesions on CT 
 
 
 
RELAPSED DISEASE  
OR PD 
 
 
 
Any new lesion or increase by 
>50% of previously involved 
sites from nadir 
 
Appearance of a new lesion(s) >1.5 cm in 
any axis, >50% increase in SPD of more 
than one node, or >50% increase in longest 
diameter of a previously indentified node 
>1cm in short axis 
Lesions PET positive if FDG-avid lymphoma 
or PET positive prior to therapy  
 
Abbreviations: CR, complete remission; FDG, [18F] fluorodeoxyglucose; PET, positron emission tomography; 
CT, computed tomography; PR, partial remission; SPD, sum of produce of the diameters; SD, stable 
disease; PD, progressive disease. 
 
*As published in Journal of Clinical Oncology [6]


 
 
 
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 Page 48 of 54 
 
APPENDIX 3 – DEFINITION OF RESPONSE CRITERIA 
 
Conventional CT response to chemotherapy will be defined as follows: 
 
COMPLETE RESPONSE (CR) 
 
Normal tumour markers, no clinical or radiological evidence of disease or surgery indicating no viable 
cancer cells in resected specimens (if surgery is done at this stage). 
 
 
PARTIAL RESPONSE (PR) (marker positive) 
 
More than 90% reduction in tumour markers and/or >50% reduction in tumour masses determined by 
radiology for at least 28 days following cessation of chemotherapy without normalisation of tumour 
markers.   
 
 
PARTIAL RESPONSE (PR) (marker negative) 
 
Normalisation of markers and residual mass (marker negative PR) for at least 28 days 
 
 
STABLE DISEASE 
 
Less than 50% reduction in tumour markers for at least 1 month following chemotherapy. 
 
 
PROGRESSIVE DISEASE 
 
Less than 50% reduction in tumour markers or progression within 28 days of stopping chemotherapy 
  
 


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APPENDIX 4 – DEAUVILLE CRITERIA 
 
Deauville criteria:- 
Visual interpretation of the PET-CT scan uses a 5-point scale. 
Baseline and PET-CT scans are scored according to uptake in sites initially involved by metastatic seminoma: 
(1) no uptake, (2) uptake = mediastinum blood pool, (3) uptake = liver, (4) moderately increased uptake > 
liver, or (5) markedly increased uptake > liver and/or new lesions.  A score of 1-3 is regarded as negative and 
4 or 5 as positive. 
 
 
 
*As published in ASH Education [10]


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     Page 50 of 54 
 
 
APPENDIX 5 – UCLH PET SCAN REQUEST FORM FOR BARTS 
 
  
  
  
  
  
  
Hospital No.: 
  
  
  
UCL HOSPITALS  
  
Surname:  
  
  
DISTRICT NUCLEAR MEDICINE SERVICE 
  
First Names: 
  
  
REQUEST FORM  
  
Date of Birth:  
  
Sex:  Male 
  
SITE (Please add): 
Address (If O.P) 
  
WARD/DEPT:  
  
  
  
UCH 
  
  
  
  
  
  
Other (specify) 
  
  
  
Outpatients 
  
?P.P. 
Yes/No 
  
  
  
Patient Tel. No. 
  
  
  
  
  
  
EXAMINATION REQUESTED: 
  
  
  
Consultant: 
JS 
  
  
PROVISIONAL DIAGNOSIS: 
  
  
  
  
  
  
  
CLINICAL HISTORY: 
  
  
  
  
  
Walking 
  
  
Patient with Metastatic seminoma  
  
Chair 
  
  
PET CT-Scan Assessment  
  
Trolley 
  
  
For attention of Dr Rizwan Syed: 
  
  
  
  
Rizwan.Syed@uclh.nhs.uk 
  
L.M.P 
  
  
Please fax the request form to 0203 447 0591 
  
Pregnancy check 
  
Visit time point:  
1. Before commencing treatment 

  
APPOINTMENT: 
  
2. Assess response during treatment 

  
Date: 
  
  
3. Staging post treatment 

  
Time: 
  
  
Requested by:  
  
  
  
Telephone no: 
  
  
  
  
  
Fax no: 
  
  
  
  
Date: 
  
SIGNED: 
(Referring consultant) 
BLEEP 
NO.: 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Car-PET Protocol – version 8.0 dated 31 Aug 2017 
APPENDIX 6 – UCLH PET SCAN REQUEST FORM FOR MOUNT VERNON 
 


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                              
 
Page 52 of 54 
 
APPENDIX 7 – SUBMISSION OF IMAGES FOR CENTRAL REVIEW AND ESCALATION PROCESS 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
Central Reviewer  
sends PDF report to 
site via email 
address provided 
Report received 
within 3wks? 
CENTRAL 
REVIEW 
Site sends image via IEP and 
faxes Request Proforma 
simultaneously to Central 
Reviewer on 020 3447 0591 and/ 
email: rizwansyed@nhs.net & 
shane.blanchflower@nhs.net  
Site emails ALL direct 
clinical trial staff involved 
including CarPET Trial 
Coordinator 
Escalation Process: 
 
1. Site contacts central reviewer 
directly after 2 weeks of submitting 
image via IEP to ensure the target 
of 3 weeks is going to be met. 
2. If no response from Central 
Review, site should inform the Trial 
Coordinator via email: bci-
carpet@qmul.ac.uk . 
3. The CarPET Trial Coordinator 
to contact via telephone and/or 
email and report back to site with 
an expected date for report. 
File report in 
patient medical 
records and plan 
patient treatment 
YES 
NO 
CarPET Trial Coordinator 
records this on Mastersheet. 
Clock starts. UCLH confirm 


 
 
 
Car-PET Protocol – version 8.0 dated 31 Aug 2017                                                                     Page 53 of 54 
 
APPENDIX 8 –IMAGING PROTOCOL 
 
Scanning Protocol 
 
1. 
Administer 350-400MBq 18FDG. 
2. 
The emission scan should start 60 minutes after tracer injection from the skull base 
to the upper thigh.  
3. 
A low dose CT should be performed for attenuation correction and anatomical 
localisation from the skull base to the upper thigh. 
 
Acquisition should be performed using the institution’s standard protocol with regard to 
time per bed position, 2D or 3D, CTAC-parameters, reconstruction parameters and 
algorithms etc.  Both attenuation corrected and non-attenuation corrected data sets should 
be reconstructed. 
 
Radiation Dosimetry 
 
The effective radiation dose associated with an administration of 400 MBq 18-FDG is 
10.0mSv (ARSAC Notes for Guidance 1998).  The CT attenuation correction using 80mA 
and 150KV will be approximately 8 mSv for scan suggested 
 
Image Data Transfer 
 
Image data must be transferred to UCLH Central Review (Dr Rizwan Syed) via the secure 
NHS IEP. 
 
The following file is required: 
 
Attenuation corrected PET data acquired from the base of the skull to the upper 
thigh 
 
Non attenuation corrected PET data acquired from the base of the skull to the 
upper thigh 
 
Low dose CT data acquired from the base of the skull to the upper thigh 
 
CT scout views are not required 
 
All files must be clearly marked with the pre-arranged filename.  The patient’s full name 
can be used when using the secure IEP system.  The trials office cannot have any 
correspondence sent to them via email or post with patient personal identifiers 
being present, only initials, date of birth and trial numbers are applicable. 
 
 
 
 


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SAP_001.pdf: 
 
 
 
SAP version 2.0: Car-PET 
10 April 2018 
Page 1 of 15 
 
Statistical Analysis Plan 
TRIAL FULL TITLE 
A multi-centre phase II study using carboplatin AUC-10 for 
metastatic seminoma with IGCCCG good prognosis disease – therapy 
directed by initial metabolic response on PET-CT (Car-PET) 
EUDRACT NUMBER 
2009-009882-33 
SAP VERSION 
2.0 
SAP VERSION DATE 
10 April 2018 
TRIAL STATISTICIAN 
Dr Shah-Jalal Sarker 
Signature  
Date 10 April 2018 
 
TRIAL CHIEF 
INVESTIGATOR 
Dr Jonathan Shamash 
Signature  
Date 10 April 2018 
 
 
 
 
 


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Document History 
Version 
Date 
Changes Made 
1.0 
1st January 2016 
First version 
2.0 
10 April 2018 
Second version 
 
 
 


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Table of Contents 
Document History ................................................................................................................................... 2 
Table of Contents .................................................................................................................................... 3 
Abbreviations and Definitions ................................................................................................................. 5 
1 
Introduction .................................................................................................................................... 6 
1.1 
Preface......................................................................................................................................... 6 
1.2 
Purpose of the Analyses .............................................................................................................. 6 
2 
Study Objectives and Endpoints ...................................................................................................... 6 
3 
Study Methods ................................................................................................................................ 7 
3.1 
General Study Design and Plan ................................................................................................... 7 
3.2 
Inclusion-Exclusion Criteria and General Study Population ........................................................ 9 
3.2.1 
Inclusion Criteria ..................................................................................................................... 9 
3.2.2 
Exclusion Criteria ..................................................................................................................... 9 
3.3 
Randomisation and Blinding ....................................................................................................... 9 
3.4 
Study Variables ............................................................................................................................ 9 
4 
Sample Size .................................................................................................................................... 10 
5 
General Considerations ................................................................................................................. 10 
5.1 
Timing of Analyses ..................................................................................................................... 10 
5.2 
Analysis Sets .............................................................................................................................. 10 
5.2.1 
Definition of Analysis Sets ..................................................................................................... 10 
5.2.2 
Protocol Deviations ............................................................................................................... 10 
5.3 
Missing Data .............................................................................................................................. 11 
5.4 
Interim Analyses and Data Monitoring ..................................................................................... 11 
5.5 
Multi-centre Studies .................................................................................................................. 11 
5.6 
Multiple Testing ........................................................................................................................ 11 
6 
Summary of Study Data................................................................................................................. 11 
6.1 
Subject Disposition .................................................................................................................... 11 
6.2 
Demographic and Baseline Variables ........................................................................................ 12 
6.3 
Concurrent Illnesses and Medical Conditions ........................................................................... 12 
6.4 
Prior and Concomitant Medications ......................................................................................... 12 
6.5 
Treatment Compliance .............................................................................................................. 12 
7 
Efficacy Analysis ............................................................................................................................ 13 
7.1 
General Principles ..................................................................................................................... 13 


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7.2 
Primary Efficacy Analysis ........................................................................................................... 13 
7.2.1 
PFS ......................................................................................................................................... 13 
7.3 
Secondary Efficacy Analysis ....................................................................................................... 13 
7.3.1 
Metabolic Response Rate ...................................................................................................... 13 
7.3.2 
Overall response .................................................................................................................... 13 
7.3.3 
Overall Survival ...................................................................................................................... 13 
8 
Safety Analysis ............................................................................................................................... 14 
8.1 
Extent of Exposure .................................................................................................................... 14 
8.2 
Adverse Events (AEs) ................................................................................................................. 14 
8.3 
Deaths, Serious Adverse Events (SAEs) and other Significant Events ....................................... 14 
8.4 
Clinical Laboratory Evaluations ................................................................................................. 14 
8.5 
Other Safety Measures.............................................................................................................. 14 
8.5.1 
Vital Signs .............................................................................................................................. 14 
9 
Reporting Conventions .................................................................................................................. 14 
10 
Technical Details ........................................................................................................................ 15 
11 
Summary of Changes to the Protocol ....................................................................................... 15 
12 
References ................................................................................................................................. 15 
 
 
 


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Abbreviations and Definitions 
 
Abbreviations 
Definitions 
AE 
Adverse event 
AUC 
Area under the curve 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
ECOG 
Eastern cooperative oncology group 
EDTA 
Ehylenediaminetetraacetic acid 
FAS 
Full analysis set 
FDG 
Fluorodeoxyglucose 
K-M 
Kaplan-Meier  
MedDRA 
Medical dictionary for regulatory activities 
NCI 
National cancer institute 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PID 
Percentage intended dose 
PR 
Partial response 
RDI 
Relative dose intensity 
SAE 
Serious adverse event 
SS 
Safety set 
 
 


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1 
Introduction 
 
1.1 
Preface 
Metastatic seminoma is a relatively infrequent disease entity. The conventional treatment for it, 
namely cisplatin and etoposide with or without bleomycin, has a progression-free survival (PFS) rate 
at 3 years of over 81% compared to 71% treated with carboplatin area under the curve (AUC) 7 [1]. 
Several studies have addressed the use of single agent carboplatin in metastatic seminoma. Studies 
have generally concluded that although PFS is inferior to that seen with cisplatin based therapy, as a 
large number of relapsing patients could be salvaged, the overall survival was unchanged and indeed 
toxicity was substantially reduced [1, 2]. 
 
The Orchid Clinical Trials Group recently completed a study in metastatic seminoma using carboplatin 
AUC-10. Twenty patients received this dose of carboplatin for metastatic seminoma, with a median 
follow up of 29.4 months. Following the closure of the study a further 20 patients have received 
carboplatin AUC-10. In total 40 patients have been treated. There have been 2 relapses to date (5%), 
compared to the 18% relapse seen within the first 2 years of treatment of 28 patients who received 
AUC 7 or less with a median follow up of 135 months. The relapsed patients were successfully 
salvaged using conventional chemotherapy. As nearly all relapses occur within 2 years of therapy, a 2 
year PFS is an appropriate endpoint for this phase II study. 
 
In this most recent study, the protocol stipulated that all patients who were not in complete 
remission by day 21 of the first cycle would receive 4 rather than 3 cycles. This led to all those who 
essentially had greater than 2B disease requiring 4 cycles. This was probably unnecessary as most 
patients achieved a complete response (CR) eventually – it just took time for the masses to shrink. 
 
It is hoped, in the Car-PET study, that by substituting conventional computed tomography (CT) for 
positron emission tomography (PET) CT a greater proportion of patients will achieve a complete 
metabolic response and therefore the 4th cycle may be avoided in more patients. This will allow 
shortening of the treatment and reduction in the use of blood products as most of the blood 
transfusions required occur during the 4th cycle of carboplatin. 
 
1.2 
Purpose of the Analyses 
These analyses will assess the safety, efficacy and toxicity of carboplatin AUC-10 in metastatic 
seminoma in a multi-centre setting. The aim is to see if, by using Fluorodeoxyglucose (FDG) PET-CT to 
assess metabolic response, the number of patients requiring 4 cycles can be reduced. 
 
2 
Study Objectives and Endpoints 
 
 
Primary Objective 
Endpoints 
2-year PFS rate 
PFS rate for carboplatin AUC-10 at 2 years 
measured from the date of study enrolment to the 
date of disease progression or death.  
 
The study result will be considered positive if the 
PFS rate for patients on carboplatin AUC-10 is 
consistent with a true difference of 15% or more 
from standard chemo i.e. if there are at least 39 
PFS patients out of the first 45 patients at 2 years. 
Secondary Objectives 
Endpoints 


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Metabolic response rate 
Proportion of patients meeting each of the 
response categories as defined in Appendix 2 of 
the protocol. 
Overall response 
Overall response at the end of the treatment 
Overall survival 
Median overall survival time measured from the 
date of study enrolment to the date of death. 
Toxicity level  
Percentage of adverse events (grade 3 or 4 
according to CTCAE version 4.03 criteria) in terms 
of treatment cycle of any type (including vomiting, 
nausea and diarrhoea). 
 
3 
Study Methods 
 
3.1 
General Study Design and Plan 
This is a single arm phase II study to assess the safety, efficacy and toxicity of carboplatin AUC-10 in 
metastatic seminoma. Up to 50 patients will be recruited into the study over four years (assuming 5 
patients may drop out for reasons other than disease progression/intolerable side effects). 45 
evaluable patients will be necessary to establish activity of carboplatin AUC10 in this setting. Patients 
will be recruited for 48 months. Patients will be followed up as part of the study for 2 years following 
completion of treatment. The end of the study will be 3 months after the date when the last patient 
has completed his final follow up visit. 
 
Prior to the commencement of treatment, the patient should have a baseline PET-CT scan and a 
contrast enhanced CT scan performed within 28 days of study entry. Patients will be treated with 
carboplatin AUC-10 every 3 weeks (3 weeks=1 cycle) and on day 17-21 of the first cycle a repeat PET-
CT scan will be performed. If the patient has a complete metabolic response (see Appendix 3 of the 
protocol), a further 2 cycles of carboplatin will be given, leading to a total of 3, and if the patient has 
not had a complete metabolic response but is responding, a further 3 cycles of carboplatin will be 
given.  
 
If a patient is showing no response to treatment then the patient will be taken off study and will 
receive conventional therapy using a cisplatin-based combination. 
 
 
 


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Figure 1: Treatment Flowchart  


 
 
 
 
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3.2 
Inclusion-Exclusion Criteria and General Study Population 
 
3.2.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Metastatic seminoma – International Germ Cell Cancer Collaborative Group (IGCCCG) good 
prognosis. 
2. Glomerular filtration rate of over 25 ml/min (creatinine clearance should preferably be 
assessed using an ehylenediaminetetraacetic acid [EDTA] clearance). 
3. Eastern cooperative oncology group (ECOG) performance status 0-3. 
4. Normal Alpha-fetoprotein (All levels of Human chorionic gonadotropin and lactate 
dehydrogenase are acceptable). 
5. Males aged greater than 18 and less than 75 years. 
6. Able to give written informed consent prior to study entry. 
7. Patients must be sterile or agree to use adequate contraception during the period of 
therapy.  
 
3.2.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:  
1. Metastatic seminoma with any non-pulmonary visceral metastases. 
2. Raised Alpha-fetoprotein. 
3. Any previous chemotherapy or radiotherapy. 
4. Currently enrolled in any other investigational drug study. 
5. Other malignancy except basal cell. 
 
3.3 
Randomisation and Blinding 
This is an open-label single arm phase II study therefore randomisation and blinding are not 
applicable. 
 
3.4 
Study Variables 
 
3.4.1 Primary and Secondary Variables 
 
3.4.1.1 Primary Efficacy Variables 
 
3.4.1.1.1. 
Progression-Free Survival (PFS) 
PFS is defined as the time between the date of enrolment to first evidence of disease progression 
based on central review or death, whichever occurs first. For patients who have not died or 
experienced disease progression at the end of study, PFS will be censored on the last date the patient 
was known to be progression-free. Patients with no post-baseline tumour assessment will be censored 
at the date of enrolment plus 1 day. The PFS time will always be derived based on scan/assessment 
dates not visit dates. 
 
3.4.1.2 Secondary Efficacy Variables 
 
3.4.1.2.1. 
Metabolic Response Rate 
One of the aims of this study is to see if, by using FDG PET-CT to assess metabolic response, the 
number of patients requiring 4 cycles can be reduced. There are currently no well validated 
metabolic response criteria for PET-CT in seminoma. Hence, we will use the criteria for the 
assessment of response developed for the evaluation of lymphoma (see Appendix 2 in the protocol). 
 


 
 
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3.4.1.2.2. 
Overall Survival 
Overall survival is defined as the time from date of enrolment to the date of death due to any cause. 
All deaths will be included, whether they occur on study treatment or following treatment 
discontinuation. For patients who have not died, OS will be censored at the date of last contact. 
Methods for handling censoring and for analysis are the same as those described for PFS. 
 
4 
Sample Size 
The primary objective is to gain a preliminary indication on whether carboplatin AUC-10 is worthwhile 
considering in a phase III study, using the PFS rate as a criterion. A’Hern’s single-stage procedure is 
used to estimate the number of patients required [3].  
 
The primary outcome is the percentage of patients progression-free at 2-years. Therefore, all patients 
must have at least 2-years follow-up (unless they have died or their disease has progressed). A Medical 
Research Council (MRC) study [1] showed that PFS rate at 3 years in standard chemotherapy, 
bleomycin, etoposide, cisplatin (BEP), is 81%. It is also known that PFS rate at 2-years and 3-years are 
the same [2]. Carboplatin AUC-10 should not therefore have a 2-year PFS rate of 75% or less, and it 
would only be worth considering in a phase III study if the true rate were 90% or more. This 
information is used in A’Hern’s single stage design to yield a sample size of 45 patients, with 80% 
power and one-sided test of significance at the 5% level. Here the statistical assumption of this design 
is that there is 80% chance of concluding that carboplatin AUC-10 is effective if the true response rate 
is 90% or more, but only a 5% chance of concluding it is effective if the response rate is 75% or less. 
To allow for a 10% drop-out rate the intention is to recruit up to 50 patients. 
 
5 
General Considerations 
 
5.1 
Timing of Analyses 
The data will be analysed at the end of the study. No formal interim analyses are planned as the 
carboplatin AUC-10 is considered to be relatively safer than the standard chemotherapy. However, 
analysis may be performed for conference presentations after all patients have been recruited and 
treated, but have not completed the follow-up time. This may only be done after recruitment of all 
patients and completion of treatment and hence unlikely to affect the study.  
 
5.2 
Analysis Sets 
 
5.2.1 Definition of Analysis Sets 
Two analysis sets will be defined: 
 
5.2.1.1 Full Analysis Set (FAS) population 
The FAS will consist of all patients who completed at least one cycle of carboplatin AUC-10 and for 
whom relevant data is available at baseline and follow up. All efficacy analyses will be performed on 
the FAS population. 
 
5.2.1.2 Safety Set (SS) population 
The SS will consist of all patients who meet the eligibility criteria and received at least one dose (cycle) 
of carboplatin AUC-10. Patients who did not receive any doses of study treatment will be excluded 
from the safety population. All safety analysis will be performed on the SS population. 
 
5.2.2 Protocol Deviations 
All-important deviations related to study inclusion or exclusion criteria, conduct of the trial, subject 
managements or subject assessment will be tabulated and listed. 


 
 
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5.3 
Missing Data 
No imputation will be performed for missing data as it is a single arm study. Data that are potentially 
spurious or erroneous will be examined under the auspices of standard data management operating 
procedures. 
 
5.4 
Interim Analyses and Data Monitoring 
There are no planned independent data monitoring committee (IDMC) reviews as the Carboplatin 
AUC-10 is considered to be relatively safer than the standard chemotherapy. However, the interim 
data is analysed for conference presentation. 
 
5.5 
Multi-centre Studies 
This is a phase II multicentre trial. It is not expected that centre will have any effect to the primary 
outcomes.  
 
5.6 
Multiple Testing 
No adjustment for multiple comparison will be performed. 
 
6 
Summary of Study Data 
Study data will be summarised using appropriate summary statistics (i.e. mean, standard deviation, 
median, and range for continuous variables, and number and proportion of patients for categorical 
variables). Summaries will be presented for the SS population. The baseline value of any variable will 
be defined as the last available value prior to the first administration of study treatment. 
 
6.1 
Subject Disposition 
A CONSORT diagram will be produced as follows (as applicable): 
 


 
 
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The number of patients enrolled will be tabulated by study site. Patient disposition will be tabulated, 
and reasons for premature discontinuation will be summarised.  
 
6.2 
Demographic and Baseline Variables 
Demographic and baseline characteristics (age; primary location; stage; ECOG PS; Tumour markers; 
BHCG; LDH; EDTA or measured creatinine clearance will be summarised. 
 
6.3 
Concurrent Illnesses and Medical Conditions 
All AEs and serious AEs (SAEs) will be coded according to the latest available Medical Dictionary for 
Regulatory Activities (MedDRA) version. The Chief Investigator may wish to group MedDRA codes 
further into more clinically meaningful groups for analysis and interpretation. Any grouping of 
toxicity codes will be signed off by the Chief Investigator.  
 
 
6.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarised in terms of frequency. Medication will be 
coded using Systematized Nomenclature of Medicine (SNOMED). 
 
6.5 
Treatment Compliance 
Treatment compliance will be presented for all patients in the SS in terms of: 
 
Median and range for each cycle length. 
 
Frequency and percentage of patients having a dose reduction. 


 
 
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 
Frequency and percentage of patients having a dose reduction due to low platelet count 
(<20). 
 
Frequency and percentage of patients discontinuing investigational medicinal product (IMP). 
 
Frequency and percentage of patients leaving the study due to disease progression or death.  
 
7 
Efficacy Analysis 
 
7.1 
General Principles 
Efficacy data will be summarised using appropriate summary statistics (i.e. mean, standard 
deviation, median, and range for continuous variables, and number and proportion of patients for 
categorical variables). CIs will be calculated as appropriate. Summaries will be presented for the FAS 
population. The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment. 
 
7.2 
Primary Efficacy Analysis 
 
 
7.2.1 PFS 
Kaplan-Meier (K-M) methodology will be used to estimate the median PFS. The median PFS and PFS 
rate for carboplatin AUC-10 at 2-years will be estimated with one-sided 95% CI to be consistent with 
one-sided test. However, 2-sided 95% CI will also be presented. The study result will be considered 
positive if the PFS rate for patients on carboplatin AUC-10 is consistent with a true difference of 15% 
or more from standard chemo i.e. if there are at least 39 PFS patients out of the first 45 patients at 2 
years. 
 
7.3 
Secondary Efficacy Analysis 
 
7.3.1 Metabolic Response Rate 
The number and percentage of subjects falling into each response category defined in Appendix 2 of 
the protocol i.e. the categories of: CR, PR marker positive, PR marker negative, stable disease, and 
progressive disease after one cycle will be descriptively tabulated. 
 
 
7.3.2 Overall response 
Overall treatment responses will be measured using the same criteria described in our previous 
phase II study 5, which are consistent with other published reports. Progressive disease is deﬁned as 
the development of new sites of disease with rising tumour markers if present. Stable disease is 
deﬁned as the lack of any new sites of disease and a <90% reduction in tumour markers, 28 days 
after chemotherapy. Marker-positive partial response (M+ve PR) is deﬁned as a >90% reduction in 
tumour markers (without normalisation) for ≥28 days, and no new sites of disease. Marker-negative 
PR (M-ve PR) is deﬁned as a normalisation of tumour markers and no new sites of disease for ≥28 
days. For those patients who have normal tumour markers before chemotherapy, a M-ve PR 
required a 50% reduction in the bi-dimensional measurements of the residual masses to be 
maintained for ≥28 days. Complete remission (CR) is deﬁned as a normalisation of tumour markers 
with a complete resolution of all sites of disease. Postsurgical outcome is deﬁned as outcome after 
surgery performed to remove all sites of disease, and patients who achieves a radiological CR to 
chemotherapy alone or has a surgically induced CR is deemed to have no evidence of disease (NED). 
 
7.3.3 Overall Survival 
Analysis methods are the same as those described for PFS in Section 7.2.1. 
 


 
 
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8 
Safety Analysis 
Safety data will be summarised using appropriate summary statistics (i.e. mean, standard deviation, 
median, and range for continuous variables, and number and proportion of patients for categorical 
variables). Summaries will be presented for the SS population. The baseline value of any variable will 
be defined as the last available value prior to the first administration of study treatment. 
 
8.1 
Extent of Exposure 
 
Sometimes the doses are recalculated on Aria - prescribing system if there has been a change in 
creatinine- these lead to minor changes and hence they are not counted as dose-reduction as they 
are all less than 10%. Exposure data will be summarised, indicating total exposure to study drug, as 
well as the number of any dose reductions. 
 
8.2 
Adverse Events (AEs) 
AEs, irrespective of relatedness, will be summarised. Verbatim descriptions of treatment-emergent 
AEs will be mapped to the appropriate thesaurus terms and summarised by mapped MedDRA term, 
and national cancer institute (NCI) CTCAE grade. For each patient’s AE, the maximum severity 
reported will be used in the summaries. SAEs, including deaths, will be summarised separately. 
Specifically, the following descriptive statistics will be generated. 
1. Incidence of SAEs. 
2. Incidence of grade 3 and 4 AEs (CTCAE, version 4.03). 
3. Incidence of all AEs of all grades.  
 
8.3 
Deaths, Serious Adverse Events (SAEs) and other Significant Events 
All deaths, SAEs and other significant events will be summarised in line listings. SAEs will be 
reconciled with the AEs. 
 
8.4 
Clinical Laboratory Evaluations 
Laboratory data will be tabulated, with values outside normal ranges identified and summarised by 
NCI CTCAE (Version 4.03) grade. Barts Normal ranges will be used as reference. The worst condition 
for each patient during the entire treatment will be reported. 
 
8.5 
Other Safety Measures 
 
8.5.1 Vital Signs 
Changes in vital signs data (if applicable) will be summarised by scheduled measurement time. Vital 
signs will include height (cm), weight (kg), temperature (degrees Celsius), blood pressure, respiratory 
rate, and heart rate.  
 
ECOG performance score will also be summarised by scheduled time point. 
 
9 
Reporting Conventions 
The mean, standard deviation, and any other statistics other than quantiles, will be reported to one 
decimal place greater than the original data. Quantiles, such as median, or minimum and maximum 
will use the same number of decimal places as the original data.  
 


 
 
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10 
Technical Details 
Analysis will be conducted using Stata v 13 (or subsequent versions). A second statistician will 
independently double check the statistical codes for the main endpoints of analysis following our 
Statistical standard operation procedure (SOP).  
 
This SAP is based on Car-PET Protocol: Master Version 8.0 dated 31st August 2017. All programs will 
be stored in the G:\Experimental Cancer Medicine\Statistics\Inhouse Unblinded\Car-PET folder until 
the end of the study at which point they will be merged with the trial master file (TMF) for archiving. 
 
11 
Summary of Changes to the Protocol 
 
12 
References 
1. Horwich A, Oliver RT, Wilkinson PM, et al.: A medical research council randomized trial of 
single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. 
MRC Testicular Tumour Working Party. British Journal of Cancer 2000; 83(12): 1623-9. 
2. Bokemeyer C, Kollmannsberger C, Stenning SP, et al.: Metastatic seminoma treated with 
either single agent carboplatin or cisplatin-based combination chemotherapy: a pooled 
analysis of two randomised trials. Br J Cancer 2004; 91(4): 683-687. 
3. A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 2001; 20(6): 
859-66.