sorce - icr
TRANSCRIPT
Developed on behalf of the NCRI Renal Clinical Studies Group
SORCE A Phase III Randomised Double-blind Study Comparing Sorafenib With Placebo In Patients With Resected Primary Renal Cell Carcinoma at High or Intermediate Risk of Relapse Clinical study protocol: RE05 ISRCTN: XXXXX EUDRACT: 2006-006079-19
CTA: 00316/0222/001-0001
Version 1.2 May 2007 (Based on MRC CTU template protocol version 3.15)
Authorised by:
Name: Professor Tim Eisen Role: Chief Investigator
Signature: Date: 15th Feb 2007
Name: Professor Patrick Royston Role: Senior Statistician
Signature: Date: 15th Feb 2007
MRC SORCE
SORCE Version 1.2
2
GENERAL INFORMATION
This document describes the SORCE trial and provides information about procedures
for entering patients into it. The protocol should not be used as an aide-memoire or
guide for the treatment of other patients; every care was taken in its drafting, but
corrections or amendments may be necessary. These will be circulated to the
registered investigators in the trial, but centres entering patients for the first time are
advised to contact the Cancer Group, MRC CTU, London to confirm they have the
most up to date version. Clinical queries relating to this trial should be referred to the
Chief Investigator.
Compliance
This trial will adhere to the principles outlined in the International Conference on
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. It will be conducted in
compliance with the protocol, MRC GCP, Data Protection Act (DPA number:
Z5886415), NHS research governance and other regulatory requirements, as
appropriate.
Sponsor
Medical Research Council
Funder(s)
Clinical Trials Advisory and Awards Committee (CTAAC): Cancer Research UK.
Bayer AG (Educational grant plus free Sorafenib/matched placebo for all patients)
Medical Research Council
Authorisation
The following persons are authorised to sign the final protocol and protocol
amendments for the sponsor: Professor Tim Eisen (Chief Investigator) and Professor
Patrick Royston (trial statistician). The SORCE trial has been scientifically approved
by CTAAC of Cancer Research UK and is thus part of the NCRN/NCRI portfolio of
cancer trials.
MRC SORCE
SORCE Version 1.2
3
TRIAL MANAGEMENT GROUP
Chief Professor Tim Eisen Email: [email protected] Investigator: Cancer Research UK Tel: 01223 40 41 91 Cambridge Research Institute Fax: 01223 40 41 99
Robinson Way Cambridge CB2 2RE
Urological Surgeons Alastair Ritchie Email: [email protected] Peter Mulders Email: [email protected] Arie Belldegrun Email: [email protected] Arnaud Mejean Email: [email protected]
Medical Oncologists Bernard Escudier Sylvie Negrier
Email: [email protected] Email: [email protected]
Barry Hancock Email: [email protected]
Histopathologist Pat Harnden Email: [email protected] Clinical Geneticist Richard Houlston Email: [email protected]
Research Assistant Olivia Baddeley Email: [email protected]
Molecular Biologist Richard Marais Email: [email protected]
Health Economist Mark Schulpher Email: [email protected]
Coordinating Centre
MRC Clinical Trials Unit Fax: +44 (0) 20 7670 4818
Cancer Group Email: [email protected]
222 Euston Road
London, NW1 2DA
MRC Clinical Trials Unit Staff
Trial Manager: Tahera Hussain Email: [email protected] Tel:+44(0)20 7670 4794
Data Manager: Tim Barlow Email: [email protected] Tel:+44(0)20 7670 4763 Trial Statistician: Patrick Royston Email: [email protected] Tel:+44(0)20 7670 4736
Project Lead: Angela Meade Email: [email protected] Tel:+44(0)20 7670 4761
For general/clinical queries, supply of trial materials and collection of data please
contact the SORCE trial manager.
The Principal Investigator (PI) for each institution will be provided with a number to
contact the Chief Investigator directly for out of hours clinical queries.
MRC SORCE
SORCE Version 1.2
4
RANDOMISATION in SORCE
ENROLMENT in TRANSORCE (UK)
Call 24 hour IVRS
IVRS Tel Dial: 0800-89-0011 then enter Trial Line system number 866-647-8511
Web address: www.TriaLine.com
SAE NOTIFICATION
Within one working day of becoming aware of an SAE, please fax a completed SAE form to the MRC
Clinical Trials Unit on: FAX : +44 (0) 20 7670 4818
MRC SORCE
SORCE Version 1.2
5
CONTENTS
1.0 Trial Schema in the UK .................................................................... 10
2.0 Summary of SORCE.......................................................................... 11
2.1 Abstract and Summary of SORCE .................................................... 11 2.1.1 Patients studied........................................................................... 11
2.1.2 Trial interventions........................................................................ 11 2.1.3 Trial aims.................................................................................... 11 2.1.4 Outcome Measures ...................................................................... 11
2.1.5 Duration of treatment .................................................................. 11 2.1.6 Sample size................................................................................. 12
2.1.7 Ancillary studies .......................................................................... 12 2.1.8 Organisation ............................................................................... 12
3.0 Background ..................................................................................... 13
3.1 Introduction .................................................................................... 13
3.2 Sorafenib ......................................................................................... 13
3.3 Rationale for SORCE ........................................................................ 15
4.0 Aims................................................................................................. 16
5.0 Institution and Investigator Selection ............................................ 16
5.1 Institution entry criteria.................................................................. 16
5.2 Institution accreditation.................................................................. 17
6.0 Patient Selection ............................................................................. 19
6.1 Enrolment in TRANSORCE prior to Surgery (UK) ............................. 19
6.2 Surgery Guidelines .......................................................................... 19
6.3 Post-Surgery Procedures................................................................. 19
6.4 Enrolment in TRANSORCE Post-Surgery (UK) ................................. 19
6.5 SORCE Inclusion Criteria ................................................................. 20
6.6 SORCE Exclusion Criteria................................................................. 20
6.7 Procedures Prior to Randomisation within SORCE .......................... 21
7.0 Enrolment in TRANSORCE (UK) and Randomisation in SORCE - Practicalities ................................................................................................ 22
7.1 Enrolment and Randomisation practicalities ................................... 22
7.2 Drug Supplies .................................................................................. 23
8.0 Treatment of patients within SORCE ............................................... 25
8.1 Introduction .................................................................................... 25
8.2 Sorafenib (generic name: BAY 43-9006) and matching placebo ..... 25 8.2.1 Treatment schedule ..................................................................... 25 8.2.2 Dose Delays and Modifications...................................................... 25 8.2.3 Management of Hypertension ....................................................... 26
MRC SORCE
SORCE Version 1.2
6
8.2.4 Grading of Hand-Foot Syndrome (Skin Toxicity) and dose modifications................................................................................................. 26 8.2.5 Grading of Other Toxicities Except Hypertension ............................ 27
8.2.6 Dose Modifications – Dose Levels.................................................. 27 8.2.7 Accountability and unused sorafenib/placebo ................................. 27
8.3 Non-trial treatment ......................................................................... 28
8.3.1 Medications permitted.................................................................. 28 8.3.2 Medication not permitted/Precautions............................................ 28 8.3.3 Precautions with Permitted Medication .......................................... 28
8.4 Co-enrolment rules.......................................................................... 29
9.0 Unblinding procedures..................................................................... 30
9.1 Emergency Unblinding................................................................... 30 9.1.1 Unblinding by the MRC CTU.......................................................... 30
10.0 Assessments during treatment ....................................................... 31
10.1 Assessments .................................................................................... 31
10.2 Progression of disease: development of local recurrence or distant metastasis............................................................................................... 32
10.2.1 Review of CT scans...................................................................... 32
10.3 Data handling .................................................................................. 33
10.4 Trial closure..................................................................................... 33
11.0 Patient withdrawal or transfer ....................................................... 34
11.1 Withdrawal from Trial Treatment.................................................... 34
11.2 Withdrawal of Consent to all further participation in the trial ........ 34
11.3 Patient transfers.............................................................................. 34
12.0 Statistical considerations ............................................................... 35
12.1 Method of Randomisation ............................................................... 35
12.2 Outcome Measures .......................................................................... 35 12.2.1 Primary....................................................................................... 35
12.2.2 Secondary................................................................................... 35
12.3 Sample Size ..................................................................................... 36
12.4 Analysis Plan ................................................................................... 37
12.5 Interim analysis for the SORCE trial ................................................ 38
13.0 Trial Monitoring .............................................................................. 39
13.1 Risk Assessment.............................................................................. 39
13.2 Monitoring at MRC CTU ................................................................... 39
13.3 Monitoring at Investigator Site ....................................................... 39 13.3.1 Direct access to data.................................................................... 39 13.3.2 On-site monitoring of participating institutions ............................... 39 13.3.3 Frequency................................................................................... 39
13.3.4 Monitoring visit procedures........................................................... 40
14.0 Safety Reporting............................................................................. 41
MRC SORCE
SORCE Version 1.2
7
14.1 Definitions ....................................................................................... 41
14.2 SORCE Exceptions ........................................................................... 42
14.3 Pregnancies whilst participating in SORCE...................................... 42
14.4 Institution/Investigator Responsibilities ........................................ 43
14.5 Investigator Assessment ................................................................. 43
14.6 MRC CTU Responsibilities ............................................................... 45
15.0 Ethical Considerations and Approval .............................................. 48
15.1 Ethical Considerations ..................................................................... 48
15.2 Ethical Approval............................................................................... 48
15.3 Patient Confidentiality..................................................................... 49
16.0 Regulatory approval ....................................................................... 50
17.0 Sponsorship and Indemnity............................................................ 50
18.0 Ancillary Studies ............................................................................. 51
18.1 TRANSORCE..................................................................................... 51
18.2 Cost-effectiveness ........................................................................... 51
19.0 Finance ........................................................................................... 52
20.0 Trial Management and Trial Committees ........................................ 52
21.0 Publication Policy ........................................................................... 53
22.0 Protocol Amendments .................................................................... 54
23.0 References...................................................................................... 55
24.0 Appendices ..................................................................................... 57
LIST OF FIGURES Figure 1: Trial entry, randomisation and treatment Figure 2: Safety flowchart
Figure 3: Diagram of relationships between trial committees
LIST OF TABLES Table 1: System used to define nuclear grade Table 2: Summary information on timing of assessments Table 3: Definitions of Safety Reporting Table 4: Definitions of Causality
MRC SORCE
SORCE Version 1.2
8
Abbreviations and Glossary AE Adverse event
AR Adverse reaction CI Chief Investigator
CI Confidence Interval
CRF Case Report Form CT Computed Tomography
CTA Clinical Trials Authorisation CTU Clinical Trials Unit DFS Disease Free Survival
EQ5D Standardised generic Instrument for use as a measure of health outcome ERC Endpoint Review Committee
EUDRACT European Union Drug Regulatory Agency Clinical Trial FBC Full Blood Count
FGF2 Fibroblast growth factor 2 Hb Haemoglobin
HE Health Economics
IC Informed Consent ICH-GCP International Conference Harmonisation Good Clinical Practise
IDMC Independent Data Monitoring Committee INR International normalised ratio
ISRCTN International standard randomised controlled trial number
IVRS Interactive Voice Response System LDH Lactate dehydrogenase
LFTs Liver function tests MFS Metastasis Free Survival
MHRA Medicines and Healthcare Regulatory Authority
MRC Medical Research Council NHS National Health Service
ONS Office of National statistics OS Overall survival
PD Progressive Disease PDGF Platelet Derived Growth Factor
PI Principal Investigator
PIS Patient information Sheet PO Per oral
PT Prothrombin PTT Prothrombin Time QOL Quality of Life
RCC Renal Cell Carcinoma RECIST Response Evaluation Criteria in Solid Tumour
SAE Serious adverse event SAR Serious adverse reaction
SOP Standard operating procedures SPC Summary of product characteristics
SSA Site specific assessment
SUSAR Suspected unexpected serious adverse reaction TMF Trial Master File
TMG Trial Management Group TSC Trial Steering Committee
U & E Urea and Electrolytes
UAR Unexpected adverse reaction VEGF Vascular Endothelial Growth Factor
VEGFR2 Vascular endothelial growth factor receptor 2 VHL Von Hippel Landau
WBC White blood count
MRC SORCE
SORCE Version 1.2
9
WHO World Health Organisation
MRC SORCE
SORCE Version 1.2
10
1.0 Trial Schema in the UK
Figure 1: Trial entry, randomisation and treatment
Suspected RCC Patientsabout to undergo nephrectomy
NEPHRECTOMY*NEPHRECTOMY*
*Patients should have had surgery at least
4 weeks but no more than 3 months prior
to treatment start date to be eligible for
SORCE PATHOLOGY Confirmation of RCC
LEIBOVICH SCORELEIBOVICH SCORE
CALCULATEDCALCULATED
High/IntermediateHigh/Intermediate
ScoreScore
RANDOMISATIONDouble blind to treatment allocation
ARM A:Placebo 3 years(414 patients)
Consent to enter SORCE
Follow-up assessments should be at 3 weeks, 6 weeks, 3 months, then three-monthly until end of the third year in study,
then 6 monthly until end of fifth year in study, then indefinitely annually thereafter
ARM C:Sorafenib 3 years(621 patients)ARM B:
Sorafenib 1 year,placebo 2 years(621 patients)
Outcome measures:
Primary:
Disease Free Survival (i.e. time from randomisation to first evidence of local recurrence or distant metastases or death from RCC).
Secondary:
RCC-specific survival time (i.e. time to death from RCC), overall survival, cost effectiveness, toxicity, biological characteristics of resected primary RCC (VHL, VEGFR2, FGF2, B-RAF, MEK,ERK), corroboration of Leibovich Prognostic Score.
Registration of
Post nephrectomy
Patients in TRANSORCE
Enrolment in TRANSORCE*
* Please note TRANSORCE is UK-specific
MRC SORCE
SORCE Version 1.2
11
2.0 Summary of SORCE
2.1 Abstract and Summary of SORCE
SORCE is a multi-centre randomised phase III double-blind placebo-controlled study
examining the efficacy and tolerability of sorafenib (Nexavar) in patients with
resected (total or partial) primary renal cell carcinoma (RCC) at high or intermediate
risk or relapse. Patients will be randomised to one of three treatment arms in the
ratio 2:3:3.
2.1.1 Patients studied
Patients who have had an RCC resected are eligible for randomisation into SORCE
providing they are at intermediate or high risk of relapse (Leibovich intermediate
score 3-5, high score 6-11) and satisfy the inclusion/exclusion criteria.
2.1.2 Trial interventions
Patients will be randomly assigned to 3 years of placebo (Arm A), 1 year sorafenib
followed by 2 years placebo (Arm B) or 3 years sorafenib (Arm C). Sorafenib will be
given at 400 mg po (per oral) bd doses. Patients with disease progression who
progress on Arms A or B within 3 years of start of treatment whilst on placebo will be
offered compassionate use of sorafenib at the standard dose of 400 mg po bd until
further progression/toxicity. This is referred to throughout the protocol as open-label
sorafenib.
2.1.3 Trial aims
SORCE aims to answer two questions. The first question is whether at least one year
of treatment with sorafenib increases DFS (disease-free survival) compared with
placebo. The second question is about the duration of sorafenib and whether three
years of treatment increases DFS compared to one year.
2.1.4 Outcome Measures
The primary outcome measure is disease free survival (DFS) (i.e. time from
randomisation to first evidence of local recurrence or distant metastases or death
from RCC). The secondary outcome measures include RCC-specific survival time (i.e.
time to death from RCC), overall survival (OS), cost effectiveness, toxicity, biological
characteristics of resected primary RCC (VHL, VEGFR2, FGF2, B-RAF, MEK, ERK) and
corroboration of Leibovich Prognostic Score.
2.1.5 Duration of treatment
The duration of treatment for all arms during the double-blind stage is a maximum of
3 years. Follow-up assessments are at 3 and 6 weeks, 3 months, then 3 monthly
until the end of the patient’s third year in the study, then 6 monthly until end of the
fifth year in study, then annually thereafter. Patients with disease progression on
placebo (Arm A or Arm B after year 1) can be offered compassionate sorafenib at the
standard dose of 400 mg po bd until further progression/toxicity.
MRC SORCE
SORCE Version 1.2
12
2.1.6 Sample size
A total of 1656 patients (Arm A: 414, Arm B: 621 and C: 621) will be recruited over 5
years
2.1.7 Ancillary studies in the UK
Patients will be asked to give consent for the collection of blood and tissue
specimens for translational research. This sub-study is an important part of SORCE
and is called TRANSORCE. Patients may be enrolled into TRANSORCE (a) prior to
planned surgery for suspected RCC, (b) post-nephrectomy if they have low risk
disease or (c) at the same time as they are randomised into SORCE. Further
information on TRANSORCE can be found in appendix 5 and in the TRANSORCE
manual of operations. Entry into TRANSORCE is not a prerequisite for randomisation
into SORCE. TRANSORCE has been reviewed and funded by Cancer Research UK
and is only open to centres in the UK.
Cost-effectiveness will be assessed using the EQ-5D questionnaire at 3, 6 and 12
weeks, and then 3 monthly until the end of the third year of treatment.
2.1.8 Organisation
The SORCE trial is sponsored by the Medical Research Council (MRC) and is co-
ordinated by the MRC Clinical Trials Unit (CTU) in London. The trial is funded by
Cancer Research UK, MRC CTU and with an educational grant from Bayer AG.
MRC SORCE
SORCE Version 1.2
13
3.0 Background
3.1 Introduction
Annually, 208,000 new cases and 102,000 deaths result each year from renal cell
carcinoma (RCC) throughout the world. The annual incidence in the UK is
approximately 6,200 and rising, with around 2,500 deaths (CRUK figures 2006).
Approximately 80% of RCC is clear cell type and 15% is papillary. RCC occurs
predominantly in patients over the age of 50 and is more common in men than
women. It is associated with risk factors such as cigarette smoking, obesity, genetic
factors and acquired cystic disease of the kidney1.
RCC is often asymptomatic (or associated with non-specific symptoms) until disease
is extensive. The majority of patients (70%) have localised disease at initial
diagnosis. Approximately 30-50% of patients develop metastatic disease after initial
nephrectomy with curative intent1. At present in primary RCC the only treatment
that is routinely used is total or partial nephrectomy. However, the value of adjuvant
immunotherapy is currently being investigated in the EORTC 30955 / HYDRA study.
Methylation or inactivating mutations or of the Von Hippel Lindau (VHL) gene are
present in around 70% of clear cell carcinomas, the commonest form of RCC.
Inactivation of the VHL gene results in up regulation of vascular endothelial growth
factor (VEGF) and platelet derived growth factor (PDGF). Elevated levels of VEGF
are also found in the less common RCC variants such as papillary cell carcinoma.
VEGF and PDGF act on cell receptors (VEGFR and PDGFR) to stimulate the formation
and stabilisation of new blood vessels which are crucial for the growth of tumours2.
Recently, the oral kinase inhibitor sorafenib (known as Nexavar) has become
available. Sorafenib inhibits several kinases known to be important in the
pathobiology of RCC including C-RAF, B-RAF, VEGFR2, VEGFR3 and PDGFR3.
3.2 Sorafenib4
Sorafenib is a potent inhibitor of Raf kinase (c-Raf IC 50 = 2nM, B-raf wild type IC50
= 25nM, B-raf mutant = 38nM) in vitro, in cells, and in vivo, with significant dose-
dependent anti-tumour activity in four different human tumour xenografts.
Additionally, sorafenib is also a potent inhibitor of VEGF-R2, in vitro, (with an IC50 of
90nM). Anti-cancer activity was observed in cancers that have Ras mutations, as
well as in cancers without Ras mutations. This suggests a potential use of this
compound in a large spectrum of cancer types, including tumours with a variety of
molecular aetiologies, all of which have not yet been defined. Observed anti-cancer
activity was cytostatic in nature, and was maintained upon continuation of dosing.
Sorafenib demonstrated significant anti-tumour activity also against large (400mg-
1g) colon and ovarian tumours, producing some tumour regressions during the
dosing period.
MRC SORCE
SORCE Version 1.2
14
Sorafenib as a single agent has been evaluated globally in 6 Phase I trials and 2
Phase II trials conducted by Bayer to date as well as the Phase III trial discussed in
section 3.3. The Phase I trials had an open-label, non-randomised, non-controlled,
dose-escalation design. The phase II trials are ongoing and include an uncontrolled
hepatoma study, and a randomised discontinuation study. The phase I single agent
clinical plan has focused on characterising the safety and pharmacokinetic profile
sorafenib in several different dosing regimens. All Phase I patients had a variety of
advanced refractory solid tumours. Studies 100313 and 100342 were conducted in
the US. In study 100313, low doses were utilized with doses ranging from 50mg
once weekly to 50 mg daily; Study 100313 was discontinued early because other
ongoing trials had already explored more intensive drug administration. The other 3
trials (100283, 100164, and 100277) were conducted outside of the US. Study
100283 allowed individual patient titration (e.g. intrapatient dose escalation) as per
protocol. Therefore, many patients in this study have been exposed to more than
one dosing regimen, In addition, this study, as per protocol, had an initial single dose
for the purpose of pharmacokinetic evaluations one week prior to starting the
planned dosing regimen. Study 100164 has an ongoing extension to explore
sorafenib in combination with docetaxel.
A database of monitored patients receiving sorafenib has been established. As of 29th
May 2004, there are 182 patients in this database who have been exposed to single-
agent sorafenib in the Bayer Phase I program at doses ranging from 50mg once
weekly to 800 mg bid continuously. The 5 most common drug related adverse events
were hand-foot skin reaction, dermatology/skin-other, fatigue, anorexia and
diarrhoea. There was an increase in the number of SAEs, discontinuations due to
AEs and especially skin toxicities as well as Grades 3 and 4, toxicities at the higher
dose levels (≥ 600 mg bid). Hence, 400 mg bid was selected as the recommended
dose for Phase II. Currently, the Phase II program includes 2 completed studies.
The phase II program was designed to explore anti-tumour efficacy in certain
tumour types as well as gain additional experience with pharmacokinetics and safety.
Study 10874 is a multicentre uncontrolled trial in advanced hepatocellular carcinoma
patients. There are 137 patients treated to date. Study 100391 is a randomised
discontinuation (RD) study and was designed to evaluate advanced refractory
tumour types, primarily, colorectal carcinoma but at the same time, explore other
tumour types. Thus far, the study has enrolled 501 patients composed of 139
colorectal, 30 renal, 34 melanoma, 4 pancreatic, 3 thyroid and variety of less
common tumour types. This study has a unique design. The course of therapy can
be categorised by 2 periods: an induction phase followed by a randomisation phase.
During the induction phase, all patients are treated with sorafenib at 400 mg twice
daily for 12 weeks. Subsequently, patients with stable disease are randomised to
either continuous dosing with sorafenib or placebo. The responders are maintained
on therapy while those with progressive disease are discontinued from study drug.
This design is to compare the rates of stable disease 12 weeks after randomisation.
MRC SORCE
SORCE Version 1.2
15
In general, available information from the ongoing Phase II studies reveal toxicities
that are similar to Phase I data. Again, the 5 most frequent drug-related toxicities
observed are hand-foot skin reaction, dermatology/skin-other, anorexia, diarrhoea
and fatigue. Anti-tumour activity was observed in both Phase I and Phase II studies.
Two partial responses were observed in the Phase I studies, one each in
hepatocellular carcinoma and renal cell carcinoma. Preliminary anti-tumour activity
was also reported in both Phase II studies with tumour shrinkage in hepatoma, CRC,
melanoma, thyroid, sarcoma, pancreatic cancer and RCC.
Data from the clinical mass-balance study have shown that, on average, less than
20% of the administered dose is excreted in the urine. This is in contrast to pre-
clinical data showing that less than 10% of sorafenib is excreted by the kidneys.
Thus, even in the presence of complete shutdown of renal clearance of the drug, it is
expected that a small increase in the exposure may be observed; one which is in the
realms of the sizeable inter-patient variability that has been observed in Phase I
trials.
3.3 Rationale for SORCE
In a large Phase III randomised placebo-controlled study (TARGETs) involving
patients with advanced RCC, sorafenib has shown a 70% rate of stable or shrinking
disease after 12 weeks on treatment. Progression-free survival was 5.8 months in
the sorafenib arm compared to 2.2 months in the placebo arm (hazard ratio of 0.51
and p-value of less ≤ 0.001)5. At this point accrual into the trial was halted and
patients in the placebo arm were offered sorafenib. Six months after crossover, the
median overall survival was 19.3 months in the sorafenib arm and 15.9 months in
the placebo arm (hazard ratio of 0.77 and p-value of 0.015)6. It should be noted
that the overall survival results are preliminary and cannot be considered statistically
significant under the O’Brien-Fleming rule. Final results are expected at the end of
2006. These observations compare favourably with those from the most aggressive
immunotherapies. However, unlike aggressive immunotherapies, sorafenib has few
side effects. In the TARGETs study only 13 out of 384 patients on sorafenib stopped
treatment due to adverse events. The Grade III/IV toxicities of treatment were
hypertension (1%), fatigue (2%), diarrhoea (1%) and hand/foot reaction (5%)6.
In view of the promising results of sorafenib when used in the advanced disease
setting, a trial in the adjuvant setting is both timely and worthwhile.
A recent analysis by Leibovich of 1671 patients who underwent radical nephrectomy
for clinically localised RCC between 1970 and 2000, demonstrated that by using a
simple scoring system, involving TNM staging, nuclear grade and presence of
necrosis, it was possible to identify a high risk cohort (374 patients or 22% of the
sample) who had a 3-year metastasis-free survival (MFS) of only 37%, and an
intermediate risk cohort (608 patients or 36% of the sample) with a 3-year
metastasis-free survival of 80%7. One important benefit of this scoring system is
that it represents very little extra work for the reporting pathologist, in addition to
MRC SORCE
SORCE Version 1.2
16
raising awareness of these factors and their definitions. Hence, the decision to use
this score in the SORCE study.
4.0 Aims
SORCE has been designed to answer two questions:
(i) Does at least one year of treatment with sorafenib increase DFS compared with
placebo: a comparison of Arm A vs Arm B and Arm C
(ii) If the answer to question (i) is yes, does an additional two years of sorafenib
(Arm C) increase DFS compared to one year of treatment (Arm B)?
5.0 Institution and Investigator Selection
In order to participate in the SORCE trial and in the TRANSORCE study, the Principal
Investigator (PI) in each centre must sign the Investigator Statement on behalf of all
staff who will be working on the trial. Staff at each centre may include urologists,
pathologists, oncologists, radiologists, pharmacists, research nurses and data
management staff.
5.1 Institution entry criteria
• The institution regularly undertakes the treatment of patients with RCC.
• The institution has an adequate number of qualified staff and adequate facilities
for the foreseen duration of the trial to conduct the trial properly and safely.
• All staff assisting with the trial are adequately informed about the protocol, the
investigational products and their trial related duties.
• The trial will be conducted in accordance with the current protocol and changes
will only be made when necessary to protect the safety, rights or welfare of
patients.
• The trial will be conducted in compliance with GCP and applicable regulatory
requirements.
• The institution will permit monitoring and auditing by staff from the MRC CTU
and Bayer AG and inspection by the appropriate regulatory authorities.
• Direct access will be made available to all trial related sites data/documents and
reports.
• The institution will maintain a local Trial Master File (TMF), which will contain
essential documents for the conduct of the trial.
• All trial data will be submitted in a timely manner and as described in the
protocol. Individual institutions may be suspended if data returns are poor or if
trial conduct is violated in other ways.
MRC SORCE
SORCE Version 1.2
17
• All Serious Adverse Events (SAEs) will be notified immediately to the MRC CTU,
except for those that the protocol identifies as not requiring immediate
notification (these should be notified on the Case Report Form (CRF) for the
trial). The initial SAE report shall be promptly followed by detailed written
reports.
• No trial data will be disclosed without the approval of the Trial Steering
Committee.
• All trial related documents will be retained for at least 5 years after the
completion of the trial.
• All pharmacovigilance data will be kept indefinitely.
In addition and in compliance with ICH GCP all institutions participating in the trial
will complete a delegation log and forward this to the MRC CTU. Each person
working on the SORCE trial must complete a section of this log and indicate their
responsibilities. The MRC CTU must be notified of any changes to trial personnel
and/or their responsibilities. An up-to-date copy of this log must be stored in the
Trial Master File at the institution and also at the MRC CTU. Finally, prior to entering
patients into the trial the MRC CTU must receive full contact details for all site
personnel working on the trial. This must be updated whenever there are changes
to trial staff or their contact details.
The Clinical Trial Authorisation (CTA) for the SORCE trial requires that the Medicines
and Healthcare Products Regulatory Agency (MHRA) be supplied with the names and
addresses of all participating investigators/institutions. Trial staff at the MRC CTU
will perform this task, hence it is vital the MRC CTU receives full contact details for all
investigators prior to their entering patients.
5.2 Institution accreditation
The following documentation must be received at the MRC CTU in order for an
institution to become an approved SORCE institution:
� Confirmation of favourable research ethics committee (REC) site-specific
assessment (SSA)
� Confirmation of Research and Development approval
� Completed investigator statement (signed by the institution PI)
� Completed delegation log (signature list and delegation of responsibilities)
� Full contact details for all site personnel
� Completed local trial master file self assessment form
� Confirmation from the MHRA that institutions/investigators have been added
to the SORCE CTA (Trial Staff at the MRC CTU will facilitate this)
MRC SORCE
SORCE Version 1.2
18
Upon receipt of this documentation, confirmation of institution approval will be sent
to the Principal Investigator by the trial team at the MRC CTU.
MRC SORCE
SORCE Version 1.2
19
6.0 Patient Selection
6.1 Enrolment in TRANSORCE prior to Surgery (UK)
TRANSORCE (the collection of tumour samples/blood) can be introduced to patients
prior to their surgery. The initial invitation should be made by the clinician
responsible for the patient. However, informed consent may then be taken by
qualified, experienced nurses according to local practice. It is good practice for the
patient to have a minimum of 24 hours after the initial invitation to participate before
being asked to sign the consent form. Enrolment in TRANSORCE is optional.
• Provide patient with TRANSORCE patient information sheet
• In consenting patients, obtain written informed consent for
o A blood sample to be taken;
o Surplus pathology samples (fixed, unfixed and or fresh-frozen,
whichever is available) to be collected;
o Permission to register with ONS for survival data and to collect a small
amount of other information (details of the surgery performed and the
tumour removed).
Further information on TRANSORCE is given in appendix 5. Please refer to the
TRANSORCE manual for details on collection, storage and transportation of both
blood and pathology samples.
6.2 Surgery Guidelines
Special surgery guidelines are detailed in Appendix 3 of this protocol. These
guidelines should be followed in all centres participating in TRANSORCE and SORCE.
6.3 Post-Surgery Procedures
Once surgery has been performed a sample of the removed tumour is inspected by a
pathologist and the patient’s Leibovich score calculated. Further information on the
Leibovich score and how to calculate it is given in Appendix 1. Patient’s with a
Leibovich score of 3-11 inclusive (i.e. at intermediate or high risk of relapse) are
potentially eligible for treatment in SORCE provided the rest of the eligibility criteria
listed below are fulfilled.
6.4 Enrolment in TRANSORCE Post-Surgery (UK)
Patients may also be enrolled in TRANSORCE post-surgery. Patients with a Leibovich
score of 0-2 inclusive (i.e. at low risk of relapse) may be enrolled, while patients not
enrolled prior to surgery may be enrolled at the same time as they are randomised
MRC SORCE
SORCE Version 1.2
20
into SORCE. As before, enrolment in TRANSORCE is optional. The procedures listed
in section 6.1 should be followed.
6.5 SORCE Inclusion Criteria
Patients must fulfil the following criteria:
• Histologically proven RCC
• No evidence of residual macroscopic disease on post-operative CT scan after
resection of RCC. Patients with clear cell or non-clear cell tumours are eligible
• Patients with “Intermediate” or “High” risk per the Leibovich score 3 to 11
(Special pathology guidelines for Leibovich scoring of tumour samples see
appendix 1)
• Subjects must be >18 years in age
• Women of childbearing age must have a negative pregnancy test and must use
adequate contraception during the treatment phase of the study and for 9
months afterwards. Women who wish to breast feed are not eligible for the
study
• Adequate bone marrow function (WBC > 3.4x109/l, platelets > 99x109/l), renal
function (creatinine < 2.5 x upper limit of normal and hepatic function (LFT <
1.5 x upper limit of normal) within 14 days prior to randomisation
• Patients should have had surgery at least 4 weeks but no more than 3 months
prior to treatment start date
• Serum Amylase < 1.5 x upper limit of normal
• Prothrombin (PT) or INR (International Normalized Ratio) and Prothrombin Time
(PTT) < 1.5 x upper limit of normal
• WHO Performance Status 0 or 1 (Appendix 2)
• Written Informed Consent obtained
6.6 SORCE Exclusion Criteria
• Prior anti-cancer treatment for RCC other than nephrectomy
• Cardiac arrhythmias requiring anti-arrhythmics (beta-blockers and digoxin are allowed), symptomatic coronary artery disease or ischaemia, myocardial infarction within the last 6 months, congestive cardiac failure > NYHA Class II
• Active clinically serious bacterial or fungal infections
• Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
• Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study
drug. Both men and women enrolled in this trial must use adequate birth control
MRC SORCE
SORCE Version 1.2
21
• Prior malignancy (except for cervical carcinoma in situ or adequately treated basal cell carcinoma)
• Concomitant medications which have adverse interactions with sorafenib: rifampin, grapefruit juice, ritonavir, ketoconazole, itraconazole and St John’s Wort.
• Patients with uncontrolled hypertension
6.7 Procedures Prior to Randomisation within SORCE
The trial should be introduced by the clinician responsible for the patient. However,
informed consent may then be taken by qualified, experienced nurses according to
local practice. It is good practice for the patient to have a minimum of 24 hours
after the initial invitation to participate before being asked to sign the consent form.
A full explanation must be given of the treatment options, including the conventional
and generally accepted methods of treatment. Check if patient has already been
enrolled in TRANSORCE, if the patient wishes to be enrolled in TRANSORCE follow
the procedures outlined in section 6.1 above.
Within 28 days prior to randomisation:
• Post operative imaging of disease by CT of chest, abdomen and pelvis
• Confirm the patient’s eligibility (except blood and urine tests which are
required within 14 days prior to randomisation)
• History and examination
• Assess WHO performance status (Appendix 2)
• Assess baseline symptoms according to NCIC Common Toxicity Criteria for
Adverse Events (CTCAE) (version 3.0) (See appendix 7).
• Check all other inclusion and exclusion criteria (Section 6.0).
Within 14 days prior to randomisation:
• Haematology (FBC), serum biochemistry (U&E, LFT, LDH, Amylase) and blood
pressure.
After obtaining written informed consent:
• Ask patient to complete first EQ-5D Health Questionnaire (See appendix 4).
Please Note:
If there is a delay of more than two weeks between randomisation and starting
treatment, a repeat clinical assessment should be performed to confirm the patient’s
fitness for treatment in SORCE.
MRC SORCE
SORCE Version 1.2
22
Table 1: Pre-randomisation investigations
Evaluation Baseline Clinical History X
FBC, U&Es, LFTs, LDH X♦
WHO performance status X
Blood Pressure X
O/E/toxicities X
CT Scan of chest, abdomen and pelvis X♠
Tumour Block X*
Fresh frozen tissue sample X*♣
Blood for DNA X*
Questionnaire X
♦Within 14 days prior to randomisation
♠Within 28 days prior to treatment
*Only for patients who have consented to participate in TRANSORCE ♣ Only for institutions participating in the fresh frozen tissue collection
7.0 Enrolment in TRANSORCE (UK) and Randomisation in SORCE - Practicalities
7.1 Enrolment and Randomisation practicalities
Enrolment in TRANSORCE and Randomisation in SORCE will be provided through a
telephone Interactive Voice Response System (IVRS) and via the internet. Either
procedure should only be performed once the patient’s written informed consent has
been obtained. More information on this system is provided in the IVRS/Internet
User Guide.
Patients may be enrolled in TRANSORCE at any of the following stages:
� Prior to surgery for suspected RCC
� Post-Surgery if their disease is found to be at low risk of recurrence using the
Leibovich score
� Post-Surgery if their disease is at intermediate or high risk of recurrence, when
they are also eligible for randomisation into SORCE
Randomisation into SORCE should only be performed once all the eligibility criteria
are confirmed (see section 6), written informed consent has been obtained and the
baseline EQ 5D questionnaire has been completed. At randomisation the patient will
be allocated to sorafenib or matching placebo in a double-blind fashion such that
MRC SORCE
SORCE Version 1.2
23
neither the Investigator, nor the patient will know which treatment is being
administered.
The IVRS system will allocate the patient’s unique patient trial identifier number.
Patients enrolled in TRANSORCE will retain the same unique trial number if they are
subsequently randomised into SORCE.
ENROLMENT IN TRANSORCE (UK)
RANDOMISATIONS IN SORCE
Via 24 Hour Randomisation Line or Internet web address: www.TriaLine.com
Activation of individual access code required
prior to first randomisation
See IVRS User Guide for instructions
Country (Group) Procedure
UK By IVRS: Dial 0800-89-0011 then enter TriaLine system number 866-647-8511
For information on the IVRS system please refer to the separate
IVRS User Guide
7.2 Drug Supplies
Participating Institutions will be provided with a start-up supply of study medication
once the institution has been approved for participation in SORCE (see section 5.0
for approval process). In order to maintain the blind, study medication (sorafenib or
matching placebo) will be labelled with a unique “bottle” number, which will be
assigned to a patient upon randomisation. Once received in the pharmacy, the drug
should be kept in a dry, safe place at a temperature below 25°C. The medication
should be stored in the original, immediate package.
MRC SORCE
SORCE Version 1.2
24
The study drug must only be used to treat patients on the SORCE trial and will only
be accessible to authorised staff. The investigator/Pharmacist must confirm the
receipt of SORCE drug supplies by signing the Drug Order Form supplied by Bayer.
Only the Investigator or a person assigned by him/her will be allowed to supply and
administer the drug to the patient. To have complete control over the distribution
and use of study drugs, drug accountability must be performed at every patient visit.
Bottles must be returned to the Investigator/Pharmacist with all unused medication.
Throughout the study, all unused material, i.e. empty bottles, unused tablets, etc.
will be accounted for. Documented destruction of drugs and containers should be
co-ordinated at the institution. One copy of the destruction certificate must be kept
in the Investigator’s file and the other copy must be sent to Bayer.
Each institution can order further treatment (during both the double-blind and open-
label phases of the study) via IVRS/Internet. More information on this is also
included in the IVRS/Internet User Guide.
MRC SORCE
SORCE Version 1.2
25
8.0 Treatment of patients within SORCE
8.1 Introduction
Patients will be randomly assigned to one of the following treatment arms:
Arm A: 3 years placebo
Arm B: 1 year sorafenib & 2 years placebo
Arm C: 3 years sorafenib
Sorafenib and placebo will be given at 400 mg po bd doses in all arms
8.2 Sorafenib (generic name: BAY 43-9006) and matching placebo
Bayer manufactures sorafenib tablets (See appendix 6 for Summary of Product
Characteristics (SmPC)). The 200 mg tablets are packed in bottles. Sorafenib
placebo tablets will be identical in appearance to the active study medication. Bayer
will supply both sorafenib and matching placebo tablets. The tablets are sufficiently
stable towards light, oxidation, thermal stress and hydrolytic degradation. The
formulation as presented is an immediate release (IR) dosage form, i.e. the active
ingredient is completely dissolved under in-vitro test conditions within a short period
of time.
8.2.1 Treatment schedule
Patients will self administer 400mg of sorafenib (2 x 200mg tablets) or matching
placebo twice a day. The tablets should be swallowed whole with a glass of water
every morning and evening (approximately 12 hours apart). The tablets should be
taken without food (at least 1 hour before or 2 hours after eating) or with a
moderate fat meal. Patients must be informed that if a dose is skipped subsequent
doses should be given as originally scheduled i.e. doses should not be doubled to
account for previous missed dose(s).
8.2.2 Dose Delays and Modifications
Doses will be delayed or reduced in the event of significant toxicities. Toxicities will
be graded using the CTCAE version 3.0 (see appendix 7).
If treatment is delayed for toxicity and there is no sign of recovery after 3 weeks
then treatment will be discontinued.
If a patient prematurely withdraws from study treatment due to toxicity then they
must be followed until complete resolution of that event and for the duration of the
follow-up portion of the protocol.
MRC SORCE
SORCE Version 1.2
26
8.2.3 Management of Hypertension
Sorafenib has the potential to raise a patient's blood pressure. If this is going to
happen it is usually evident within 6 weeks of starting sorafenib. All patients who are
in the randomised portion of the study or receiving open label sorafenib should have
their blood pressure monitored weekly during the first 6 weeks of treatment (via
their GP/practice nurse if possible). If a patient's blood pressure is consistently
above 150/90 then anti-hypertensive medication should be started.
Patients experiencing hypertension should be treated according to local hypertension
control guidelines. Below is a suggested guideline:
Blood pressure measurements should be made on at least 2 separate occasions prior
to starting antihypertensive therapy. Antihypertensives should be considered in
patients who have a sustained systolic blood pressure of > 160mmHg or a sustained
diastolic blood pressure of > 100mmHg.
A suggested anti-hypertensive protocol is:
First Line: Bendrofluazide 2.5mg po od (if thiazide diuretics not contraindicated)
or escalate to Amlodipine 10 mg po od if already on Amlodipine.
Ca2+ channel blocker (eg Amlodipine 5mg po od) if thiazide diuretics
are contraindicated.
Second line: If patient remains hypertensive after 4 weeks and has had a small
response to first line antihypertensive, consider REPLACING with
another class of antihypertensive. If severe hypertension seek
specialist advice.
8.2.4 Grading of Hand-Foot Syndrome (Skin Toxicity) and dose
modifications
Patients experiencing Hand-Foot syndrome should have their signs and symptoms
graded according to the following system:
Skin toxicity Symptoms
Grade I Minimal skin changes or dermatitis (e.g., erythema) without pain
Grade II Skin changes (e.g., peeling, blisters, bleeding, edema), or pain, not interfering with function
Grade III Ulcerative dermatitis or skin changes with pain interfering with function
MRC SORCE
SORCE Version 1.2
27
Skin Toxicity
Grade I Maintain dose level
Grade II 1st episode Maintain dose level
Apply symptomatic relief
2nd/3rd episode or lasting > 7 days
Interrupt treatment until resolved to grade I Decrease one dose level on resuming treatment
4th episode Discontinue treatment
Grade III/IV
1st/2nd episode Interrupt until resolved to grade I Decrease one dose level on resuming treatment
3rd episode Discontinue treatment
8.2.5 Grading of Other Toxicities Except Hypertension
Grade I Maintain dose level
Grade II 1st episode Maintain dose level
2nd/3rd episode or lasting > 7 days
Investigator may interrupt until resolved to grade I Decrease one dose level on resuming treatment
4th episode Discontinue treatment
Grade III/IV
1st/2nd episode Interrupt until resolved to grade II Decrease one dose level on resuming treatment
3rd episode Discontinue treatment
NB If no recovery after 3 weeks then treatment will be discontinued.
8.2.6 Dose Modifications – Dose Levels
The following are the dose levels in SORCE:
Starting dose: 400mg bd
First dose reduction: 400mg od
Second dose reduction: 400mg od on alternate days
8.2.7 Accountability and unused sorafenib/placebo
Study staff will monitor administration of study medication on the days that the
subjects are at the clinic for study visits. The dose and schedule of sorafenib/
placebo administered to each subject will be recorded on the Treatment Form (RE05
Form 5). Reasons for dose delay, reduction or omission will also be recorded in the
CRF. A complete dispensing log for each subject will be maintained for all
sorafenib/placebo (including batch number) dispensed.
Accountability has to be determined for all tablets of study medication (sorafenib or
placebo). To facilitate this accountability subjects must be instructed to return all
medication packaging including unused study medication and all empty bottles.
MRC SORCE
SORCE Version 1.2
28
The number of tablets returned, at each visit, must be counted in order to determine
compliance i.e. whether the number of tablets returned are consistent with the
number of tablets administered minus the number of tablets taken (according to the
number of days between visits). The reason for any discrepancy should be recorded
on the drug dispensing log and the CRF. All returned / unused study medication that
has been accounted for may be destroyed by the site. A record must be kept of this
destruction.
8.3 Non-trial treatment
8.3.1 Medications permitted
• Treatment with non-conventional therapies (e.g., herbs or acupuncture), and
vitamin/mineral supplements is acceptable, provided that they do not
interfere with the study endpoints in the opinion of the Investigator
• Patients may receive palliative and supportive care for any underlying illness
• Patients receiving bisphosphonates as a prophylaxis for osteoporosis may
continue while on trial treatment and subsequently with open-label sorafenib
• Best Supportive Care which may include analgesics, nutritional support, and
other non-anti-neoplastics
8.3.2 Medication not permitted/Precautions
• Rifampicin
• St. John’s Wort (Hypericum perforatum)
• Any other investigational therapy while on protocol treatment or within
30 days prior to their first dose of sorafenib
• Bone marrow transplant or stem cell rescue
• Any drug (licensed or investigational) that targets angiogenesis,
especially VEGF or VEGF-Receptors (e.g., Bevacizumab)
• Any drug (licensed or investigational) that targets Ras-pathway or EGFR
• Any anti-cancer therapy (chemotherapy, immunotherapy, signal
transduction inhibition or hormonal therapy) except bisphosphonates
8.3.3 Precautions with Permitted Medication
• Biological response modifiers, such as G-CSF or GM-CSF, within 3 weeks
prior to study entry or during study (G-CSF and other haematopoietic
growth factors may only be used in the management of acute toxicity
such as febrile neutropenia, when medically indicated or at the
discretion of the Investigator)
MRC SORCE
SORCE Version 1.2
29
8.4 Co-enrolment rules
If a patient has progressed on SORCE and come off that trial treatment they may be
considered for entry into another clinical trial. Follow-up within SORCE will still be
required.
MRC SORCE
SORCE Version 1.2
30
9.0 Unblinding procedures
Patients who have disease progression within the 3 year trial treatment period should
stop treatment and be unblinded through IVRS. If the patient is receiving placebo
they can be offered compassionate use of open-label sorafenib. This is described
further in section 10.2. Otherwise, unblinding is generally strongly discouraged
during treatment.
9.1 Emergency Unblinding
While the safety of patients in the SORCE trial should always take priority,
maintenance of blinding is crucial to the integrity of the trial. Investigators should
only break the blind when information about the patient’s trial treatment is clearly
necessary for the appropriate medical management of the patient. Further
information on emergency unblinding can be found in the IVRS/Web User Guide.
The reason for emergency unblinding will be collected on the Emergency Unblinding
Form (RE05 Form 14)
9.1.1 Unblinding by the MRC CTU
CTU staff who are not involved in the day to day running of the trial will be
responsible for unblinding possible SUSARs and notable events that remain unblinded
for notification to the regulatory authorities (MHRA and main REC in the UK) and
Bayer.
MRC SORCE
SORCE Version 1.2
31
10.0 Assessments during treatment
10.1 Assessments
All assessments and trial procedures must be performed in compliance with the most
up to date version of the protocol, including principles of ICH-GCP, any relevant
research governance and other regulatory requirements as appropriate.
Table 2.0: Summary information on timing of assessments Evaluation
Time points
Baseline
Visit 1
3 weeks
Visit 2
6 weeks
Visit 3
3 months
Visit 4
Every three
months
thereafter Visit 5
Other
Visit 6
Clinical History X
FBC, U&Es, LFTs, LDH
X♦ X X X X* Annually thereafter
WHO
performance status
X X X X X* After 3 years,
6 monthly until 5th year,
then annually
Blood Pressure X
X X X X* As above
O/E/toxicities X
X X X X* As above
CT Scan of
chest, abdomen and
pelvis
X♠ CT scan of chest
and abdomen (but not pelvis) should
be assessed
6 monthly during the first three years
of study
X-ray of the
chest
X 6 monthly
after visit 4
in years 1-5 and annually
thereafter
Tumour Block X**
Fresh frozen tissue sample
X**♣
Blood for DNA X**
Questionnaires X
X X X X*
*Up to 3 years ♦Within 14 days prior to randomisation
♠Within 28 days prior to treatment
** Only for patients who have consented to participate in TRANSORCE
♣ Only for institutions participating in the fresh frozen tissue collection
MRC SORCE
SORCE Version 1.2
32
10.2 Progression of disease: development of local recurrence or
distant metastasis
Patients are assessed via a CT of their chest and abdomen 6 monthly during the first
three years of SORCE, and also via chest x-ray at 3 months and then 6-monthly up
to 3 years. This means that patients have either a CT scan or chest x-ray every 3
months during the first 3 years of the study. X-rays of the chest replace CT scans 6-
monthly during years 4 and 5 and annually thereafter. The CT scans and X-rays
should be assessed using RECIST criteria (please see Appendix 8). If a patient
should experience clinical signs of progressive disease (PD) at any point, this should
be confirmed via CT/X-ray or a positive biopsy.
If PD is confirmed the treatment blind will be broken, and the patient will be
withdrawn from SORCE treatment to allow appropriate treatment for advanced RCC
that is consistent with international and local guidelines. Follow-up within SORCE will
continue unless the patient explicitly withdraws consent to follow-up. Further
information on how to report disease progression using IVRS is available in the IVRS
User Guide.
If the patient was receiving treatment with placebo prior to progression, and there
are no other suitable therapy options for advanced RCC, they can be offered open-
label sorafenib on compassionate grounds at the standard dose of 400mg po bd.
The patient will revert back to the visit schedule followed during their first 6 weeks
on protocol treatment (see page 30 for further details). Patients will continue
sorafenib treatment until further PD or toxicity.
Any patient that experiences PD who is either receiving sorafenib or who has completed the first 3 years of protocol treatment part of SORCE will not be offered
further sorafenib. Follow-up within SORCE will continue unless the patient withdraws consent.
10.2.1 Review of CT scans
In order to demonstrate consistency across the three arms of SORCE in terms of a)
the percentage of patients who indeed had no evidence of metastatic disease at
study entry and b) evidence on which a determination of PD is based a proportion of
CT scans will be independently reviewed.
Retention of copy CT scans is mandatory in all patients at the following time points:
1) Post surgery baseline CT scan
2) First CT scan taken indicating PD
Retention of copies of CT scans taken at all other times is requested but not
mandatory. CT scans should be stored at the institution if possible.
MRC SORCE
SORCE Version 1.2
33
10.3 Data handling
CRFs are on non carbon required paper (NCR); these should be filled in ink and the
top copy of all CRFs should be returned to the MRC CTU for data entry and statistical
analysis within one month of the form being due (SAE forms must however be
returned within one working day, further information is available in section 14). The
remaining copy is to be retained at the local institution. Data stored at the MRC CTU
will be checked for missing or unusual values (range checks) and checked for
consistency over time. If any such problems are identified, a data clarification form
(DCF) will be returned to the local site by post or fax for correction. The exact
procedures for data clarification and the amendment of CRFs will be described in the
trial specific SOPs and instructions will be sent to all SORCE institutions as soon as
they have been approved to participate in the trial. MRC CTU will also send
reminders for any overdue data.
10.4 Trial closure
The trial will be considered closed for regulatory purposes after the last patient
entered has completed their protocol treatment. Further observational follow-up of
all patients enrolled in the trial may continue indefinitely. This will initially be via
hospitals and clinics, but in the longer term may exploit national registers.
MRC SORCE
SORCE Version 1.2
34
11.0 Patient withdrawal or transfer
In consenting to the trial, patients are consenting to trial treatment, trial follow-up
and data collection. However, a patient has the right to withdraw consent for
participation in any aspect of this trial at any time. They may refuse to take certain
treatments or attend scheduled follow-up visits. Clear distinction must be made as
to whether the patient is withdrawing from trial treatments/procedures whilst
allowing further follow-up, or whether the patient refuses any further trial
treatments/procedures and follow-up participation. In all instances the staff at the
institution must inform the MRC CTU immediately in writing.
11.1 Withdrawal from Trial Treatment
A patient may withdraw, or be withdrawn, from trial treatment for the following
reasons:
• Progression whilst on therapy
• Unacceptable toxicity
• Intercurrent illness which prevents further treatment
• Withdrawal of consent for treatment by patient
• Any alterations in the patient’s condition which justifies the discontinuation of
treatment in the investigator’s opinion.
Patients should however remain in the trial, following the same visit schedule, for the
purposes of follow-up and data analysis.
11.2 Withdrawal of Consent to all further participation in the trial
If a patient explicitly states their wish not to contribute further data to the study, the
institution should inform the MRC CTU in writing and the reason for withdrawal of
consent should be documented by the investigator in the patient’s CRF.
11.3 Patient transfers
For patients moving from the area, every effort should be made for the patient to be
followed-up at another participating trial institution and for this institution to take
over responsibility for the patient. A copy of the patient’s CRF will need to be
provided to the new institution. The patient will have to sign a new consent form at
the new site, and until this occurs, the patient remains the responsibility of the
original institution. If the investigator moves, appropriate arrangements should be
made to arrange for trial follow-up to continue at the institution.
MRC SORCE
SORCE Version 1.2
35
12.0 Statistical considerations
12.1 Method of Randomisation
Patients will be allocated to one of arms A, B and C (see Sample size section below
for definition) in the proportions of 2:3:3 using random stratified randomisation. A
small number of clinically important stratification factors will be used. To decrease
determinability of assigned treatments, the factors are not listed here.
12.2 Outcome Measures
12.2.1 Primary
The primary outcome measure is disease-free survival (DFS), the interval from
randomisation to first evidence of local recurrence or distant metastases or death
from RCC.
12.2.2 Secondary
The first three outcomes listed below relate to efficacy. The fourth relates to cost-
effectiveness. The fifth relates to safety. The remainder are primarily of scientific
interest.
• Metastasis-free survival (MFS) - the interval from randomisation to first
evidence of metastases or death from RCC
• RCC specific survival time, i.e. the time from randomisation to death from
RCC
• Overall survival, i.e. the time from randomisation to death from any
cause, including RCC
• Cost effectiveness (health economics)
• Toxicity
• Biological characteristics of resected primary RCC (VHL, VEGFR2, FGF2, B-
RAF, MEK, ERK): Tumour samples will be examined for activation of
relevant signalling pathways, and their association with outcome will be
studied (TRANSORCE)
• Genetic epidemiology: Tumour tissue and paired constitutional DNA from
the tumour sample will be analysed to examine the relationship between
tumour genotypes, expression, and outcome and between constitutional
genotype and outcome
• Corroboration of Leibovich prognostic score
MRC SORCE
SORCE Version 1.2
36
12.3 Sample Size
SORCE will compare three arms: Arm A (control: placebo for 3 years or until
progression of RCC); Arm B (experimental arm 1: 1 year of sorafenib and 2 years of
placebo or until progression of RCC); Arm C (experimental arm 2: 3 years of
sorafenib or until progression of RCC). The trial aims to answer two questions.
Question 1 is the primary question and forms the basis of the sample size
calculation. Question 2 concerns duration of treatment; the power for this question is
calculated according to the number of patients determined for Question 1.
QUESTION 1: Does at least one year of treatment with sorafenib increase DFS
compared with placebo?
The sample size was calculated using the ART software8 assuming a hazard ratio of
0.75 between arm A and arms B and C combined. For this part of the calculation, it
was assumed conservatively that the 2 additional years of sorafenib treatment in arm
C do not increase DFS compared with arm B. The estimated DFS at 3 years for
patients in arm A is assumed to be 63.5%. This figure is estimated from Leibovich et
al (2003), restricted to the intermediate and poor prognostic groups. It is assumed
that patients are recruited over a period of 5 years and followed up for a further 3
years (total trial duration 8 years). To show a clinically important improvement in 3
year DFS from 63.5% to 71% (HR=0.75) with sorafenib requires 608 events for DFS
in 1656 patients (414 patients in arm A and 621 in each of arms B and C), using a
logrank test with 90% power and 5% two-sided significance level.
It is expected that the main data analysis for Question 1 will take place within one
year after completion of planned follow up.
QUESTION 2: For patients in arms B and C who receive sorafenib for at least one
year and who do not suffer an event for DFS during that year, does an additional two
years of sorafenib increase DFS compared with placebo?
The time origin for Question 2 is 1 year after randomisation. For Question 2, patients
are recruited over 5 years and followed up for a further 3 years. The sample size for
Question 2 is the number of patients in Arms B and C still receiving treatment one
year after randomisation, and is estimated to be 1030 (assuming drop-out is caused
only by an event for DFS). The relevant survival distribution is of DFS conditional on
surviving to 1 year without an event for DFS. Assuming a 5% significance level, the
power to detect a hazard ratio of 0.75 between arms B and C is 51% (or 66% if
follow up were extended by an additional 5 years.)
No allowance has been made for drop-out or sub-optimal adherence to treatment.
However, as a sensitivity analysis of the power for Question 2, we allowed a 10%
dropout in the first year, leaving 927 patients for answering Question 2 instead of
MRC SORCE
SORCE Version 1.2
37
1030. The power was reduced from 51% to 47% (from 66% to 62% for a 13-year
trial).
Further details of the sample size and power calculations are available on request
from the SORCE trial statistician at the MRC CTU.
12.4 Analysis Plan
All analyses will be performed on an intention-to-treat basis, i.e. all patients
randomised will be included, and all patients’ data will be analysed according to their
randomised treatment groups irrespective of the treatment they actually received.
Time-to-event curves for DFS, RCC-specific survival and overall survival will be
estimated using the Kaplan-Meier technique. For analysis of DFS and RCC-specific
survival, deaths due to other causes will be regarded as censored observations. To
address Question 1, the survival distributions of patients in arms A and B/C will be
compared according to a two-sided logrank test. A two-sided 95% confidence
interval for the hazard ratio will be calculated, both univariately and adjusted for
major prognostic factors including the Leibovich prognostic score.
To answer Question 2, only patients in arms B/C without an event for DFS at 12
months and receiving at least 1 year of sorafenib will be included in the analysis. A
closed test approach will be adopted such that the null hypothesis for Question 2 will
not be tested unless the null hypothesis for Question 1 is rejected at the 5% level.
The time origin will be set at randomisation plus 12 months. The logrank test and
confidence intervals for the effect of 2 years’ additional sorafenib treatment will be
calculated as for Question 1.
Possible interactions between treatment and prognostic factors will be investigated in
a hypothesis-generating mode. To maximise power, continuous factors will be kept
continuous in all analyses involving prognostic factors.
A full analysis plan will be developed before the final analysis is performed.
MRC SORCE
SORCE Version 1.2
38
12.5 Interim analysis for the SORCE trial
According to Peto et al (1976)9, the advantage of interim analyses is the guarantee
that in the rare cases when an active treatment is much better or much worse than
the placebo arm, the trial will be terminated. With interim analyses, adjustment
must be made to the significance level for multiple ‘looks’ at the data, including the
definitive analysis of the data. The advantage of not performing analyses until the
end of the designed follow-up period is that if one treatment is only moderately
superior or inferior, a statistically significant difference is more likely to be found than
if several interim analyses had been done (i.e. power is higher). The reason for this
is that the adjustment to the significance level for multiple analyses reduces the
power of the final test.
A simple compromise that we plan to use in the SORCE trial is to perform just two
interim analyses using a stringent two-sided significance level of 0.001 for each
analysis of the primary outcome measure. The results will be interpreted only as
guidance for continuing or stopping the trial, and will be considered in the light of
analyses of the secondary outcome measures (particularly RCC-specific survival).
The interim tests are equivalent to using a threshold chi square statistic of 10.8 for
comparing two groups, close to the chi square value of 9 suggested by Peto et al
(1976, p. 611)9. The tests will detect only large differences in treatment efficacy.
The test threshold is sufficiently stringent to mean that the test statistic in the
definitive analysis will need essentially no adjustment for multiple testing in the
interim analyses.
The interim analyses will be done after one third and two thirds of the planned 608
events for DFS have accrued, i.e. after approximately 200 and 400 events. Because
events will accrue at an increasing rate over the trial period, the first of these
analyses will take place after about 3-4 years and the second after about 5-6 years.
The results will be made available for review by the Independent Data Monitoring
Committee (IDMC) at their subsequent meetings. Comparisons relevant to Question
1 will be made, i.e. between arms A (placebo) and B/C combined (sorafenib 1/3
years).
The IDMC will of course review the accumulating safety and efficacy data at regular
intervals (at least annually) for evidence of possible harm of sorafenib. However, we
do not propose any additional formal stopping rules based, for example, on SUSAR
rates or toxicities.
MRC SORCE
SORCE Version 1.2
39
13.0 Trial Monitoring
13.1 Risk Assessment
The MRC CTU has performed a risk assessment to assess the impact of trial
participation on the rights and safety of patients, and the reliability of trial results.
This has guided the development of procedures in the trial with respect to informed
consent, confidentiality and trial monitoring.
13.2 Monitoring at MRC CTU
The MRC CTU will conduct day-to-day central monitoring of the trial. The MRC CTU
staff will:
• review when appropriate copies of source documents (e.g. pathology forms)
to verify data consistency, completion and validity with CRF data
documentation
• perform data entry (database) plausibility checks for validity and consistency
of data
• identify missing or inconsistent data
• identify and discuss random or systematic errors occurring during the course
of data collection
• check that CRFs are completed by authorised persons
• review recruitment rates
13.3 Monitoring at Investigator Site
13.3.1 Direct access to data
Collaborating institutions should be aware that direct access to patient data by MRC
CTU or regulatory agency staff may be required for trial-related monitoring or audit.
Patient consent for this will be obtained as part of the general trial consent process.
13.3.2 On-site monitoring of participating institutions
Investigators must agree to on-site monitoring on the investigator statement.
Details about the organisation, content, and conduct of these on-site visits are given
in this section.
13.3.3 Frequency
• A visit may be made during the trial to any centre. The guideline monitoring plan
is as follows:
MRC SORCE
SORCE Version 1.2
40
� all larger institutions with expected overall accrual of 30 patients or more with
on-site monitoring of 10% of patients after the entry of at least 10 patients;
� 10% of all other institutions chosen randomly, after entry of the first patient.
10% of patients at these centres will also be monitored.
� Those institutions found to have poor compliance (e.g. poor or late
documentation).
NB: Potentially, ALL participating institutions may be monitored in this way.
The purpose of these visits is:
• to verify that the rights and well-being of patients/participants are protected
• to verify accuracy, completion and validity of reported trial data from the
source documents
• to evaluate the conduct of the trial within the institution with regard to
compliance with the currently approved protocol, GCP and with the applicable
regulatory requirements
13.3.4 Monitoring visit procedures
The MRC CTU will give the Principal Investigator adequate notice of the on-site visit
to allow adequate time, space and staff. The institution is responsible for ensuring
that all relevant materials are available for review including the trial master file, case
report forms and patient source documents.
Adequate time should be taken to discuss any trial related issues and any problems
with compliance e.g. CRF completion, timeliness of data return, compliance with the
protocol and follow-up guidelines.
Implausible or missing data must be corrected or supplemented by the responsible
person named on the delegation log.
The principal investigator will be reminded of the obligations to immediately report
serious unexpected adverse events and their outcome.
NB: Potentially, ALL patients may be monitored in this way.
MRC SORCE
SORCE Version 1.2
41
14.0 Safety Reporting
ICH GCP requires that both investigators and sponsors follow specific procedures
when notifying and reporting adverse events/reactions in clinical trials. These
procedures are described in this section of the protocol. Section 14.1 lists
definitions, section 14.2 gives details of the institution/investigator responsibilities
and section 14.3 provides information on MRC CTU responsibilities.
14.1 Definitions
The definitions used in this protocol comply with EU Directive 2001/20/EC and ICH-
GCP10,11.
Table 3: Definitions of Safety Reporting
Term Definition
Adverse Event (AE) Any untoward medical occurrence in a patient or clinical trial subject to
whom a medicinal product has been administered including
occurrences which are not necessarily caused by or related to that
product.
Adverse Reaction (AR)
Any untoward and unintended response to an investigational medicinal
product related to any dose administered.
Unexpected Adverse
Reaction (UAR)
An adverse reaction, the nature or severity of which is not consistent
with the information about the medicinal product in question set out in
the summary of product characteristics (or Investigator brochure) for
that product.
Serious Adverse Event
(SAE) or Serious Adverse
Reaction (SAR) or
Suspected Unexpected
Serious Adverse Reaction
(SUSAR)
Respectively any adverse event, adverse reaction or unexpected
adverse reaction that:
• results in death
• is life-threatening*
• requires hospitalisation or prolongation of existing hospitalisation**
• results in persistent or significant disability or incapacity
• consists of a congenital anomaly or birth defect
MRC SORCE
SORCE Version 1.2
42
Clarifications and Exceptions
*The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which
the patient was at risk of death at the time of the event; it does not refer to an event
which hypothetically might have caused death if it were more severe.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay,
even if the hospitalisation is a precautionary measure for continued observation.
Hospitalisations for a pre-existing condition (including elective procedures that have
not worsened) do not constitute an SAE.
Medical judgement should be exercised in deciding whether an AE/AR is serious in
other situations. Important AE/ARs that are not immediately life-threatening or do
not result in death or hospitalisation but may jeopardise the subject or may require
intervention to prevent one of the other outcomes listed in the definition above,
should also be considered serious.
14.2 SORCE Exceptions
Disease progression or death as a result of disease progression are not considered to
be SAEs and should be reported on the First Progression Form (RE05 Form 9) and /
or the Death Form (RE05 Form 11).
Due to the seriousness of the disease in this study, the following situations that fulfill
the definition of an SAE are excluded from expedited notification on an SAE form and
should be reported on the Treatment Form (RE05 form 5)
• Elective hospitalisation and surgery for treatment of RCC or its complications.
• Elective hospitalisation to simplify treatment or procedures.
• Elective hospitalisation for pre-existing conditions that have not been
exacerbated by trial treatment
14.3 Pregnancies whilst participating in SORCE
Pregnancy occurring during a patient’s participation in the SORCE trial, although not
considered an SAE, must be notified to the MRC CTU within the same timelines as an
SAE (within one working day) on a Pregnancy Monitoring Form (RE05 form 14). The
outcome of a pregnancy should be followed up carefully and any abnormal outcome
of the mother or the child should be reported. This also applies to pregnancies
following the administration of the investigational product to the father prior to
sexual intercourse.
MRC SORCE
SORCE Version 1.2
43
14.4 Institution/Investigator Responsibilities
All non-serious AEs/ARs, whether expected or not, (and all SAEs that have been
excluded from expedited notification) should be recorded in the toxicity (symptoms)
section of the Treatment Form (RE05 Form 5) and sent to the MRC CTU within one
month of the form being due.
The severity (i.e. intensity) of all AEs/ARs (serious and non-serious) in this trial
should be graded using CTCAE v3.0 (http://ctep.cancer.gov/reporting/index.html). A
flowchart is given at the end of this section to help explain the notification
procedures (page 47). Any questions concerning this process should be directed to
the MRC CTU in the first instance.
14.5 Investigator Assessment
Seriousness Assessment
When an AE/AR occurs the investigator responsible for the care of the patient must
first assess whether the event is serious using the definitions given in Table 4. If the
event is serious and not exempt from expedited reporting, then an SAE form must be
completed and the MRC CTU notified. All pregnancies must also be reported in an
expedited fashion on an SAE form.
Causality and Expectedness Assessment
While the safety of patients in the SORCE trial should always take priority,
maintenance of blinding is crucial to the integrity of the trial. Investigators should
only break the blind when information about the patient’s treatment is clearly
necessary for the appropriate medical management of the patient. Investigators
should therefore evaluate the causality and expectedness of all serious
events/reactions as though the patient was on active drug. Please see section 9.1
for emergency unblinding procedures.
Causality definitions are given in Table 4. There are 5 categories: unrelated,
unlikely, possible, probable and definitely related. If the causality assessment is
unrelated or unlikely to be related the event is classified as a SAE. If the causality is
assessed as possible, probable or definitely related then the event is classified as a
SAR.
MRC SORCE
SORCE Version 1.2
44
If the event is a SAR the Investigator must also assess the expectedness of the
event. The investigator should evaluate the expectedness as the though the patient
was on active drug. If a SAR is assessed as being unexpected it becomes a SUSAR.
To act as a guide, the following adverse events have been reported in patients taking
sorafenib:
hypertension (grade I/II: 7%, Grade III/IV: 1%)
fatigue (grade I/II: 16%, Grade III/IV: 2%)
diarrhoea (grade I/II: 29%, Grade III/IV: 1%)
hand/foot reaction (grade I/II: 21%, Grade III/IV: 5%)
rash (grade I/II: 31%, Grade III/IV: 1%)
alopecia (grade I/II: 23%, Grade III/IV: 0%)
flushing (grade I/II: 6%, Grade III/IV: 0%)
Expectedness Assessment
The investigator responsible for the care of the patient must assess the expectedness
of events that are possibly, probably or definitely related to trial therapy. The
investigator should evaluate the expectedness as though the patient was on
sorafenib.
Table 4 Definitions of causality
Relationship Description Event Type
Unrelated There is no evidence of any causal relationship SAE
Unlikely There is little evidence to suggest there is a causal relationship
(e.g. the event did not occur within a reasonable time after
administration of the trial medication). There is another
reasonable explanation for the event (e.g. the patient’s clinical
condition, other concomitant treatment).
SAE
Possible There is some evidence to suggest a causal relationship (e.g.
because the event occurs within a reasonable time after
administration of the trial medication). However, the influence
of other factors may have contributed to the event (e.g. the
patient’s clinical condition, other concomitant treatments).
SAR
Probable There is evidence to suggest a causal relationship and the
influence of other factors is unlikely.
SAR
Definitely There is clear evidence to suggest a causal relationship and
other possible contributing factors can be ruled out.
SAR
Notification
The MRC should be notified within one working day of the investigator becoming
aware of an event that requires expedited reporting. Investigators should notify the
MRC SORCE
SORCE Version 1.2
45
MRC CTU of all SAEs occurring from the time of randomisation until 30 days after the
last protocol treatment administration. SARs and SUSARs must be notified to the
MRC CTU indefinitely (i.e. no matter when they occur after randomisation).
Notification Procedure:
1. The SAE form must be completed by the Investigator (consultant named on the
signature list and delegation of responsibilities log who is responsible for the
patient’s care), with due care being paid to the grading, causality and
expectedness of the event as outlined above. In the absence of the responsible
investigator the form should be completed and signed by a member of the site
trial team. The responsible investigator should subsequently check the SAE form,
make changes as appropriate, sign and then re-fax to the MRC CTU as soon as
possible. The initial report shall be followed by detailed, written reports as
appropriate.
2. Send the SAE form by fax to the MRC CTU
Fax Number: + 44 (0) 20 7670 4818
3. Follow-up: Patients must be followed-up until clinical recovery is complete and
laboratory results have returned to normal or baseline, or until the event has
stabilised. Follow-up should continue after completion of protocol treatment if
necessary. Follow-up information should be noted on a further SAE form by
ticking the box marked ‘follow-up’ and faxing to the MRC CTU as information
becomes available. Extra, annotated information and/or copies of test results
may be provided separately. The patient must be identified by trial number,
date of birth and initials only. The patient’s name should not be used on any
correspondence.
4. Staff at the institution must notify their local research ethics committee (LREC)
of the event (as per the institutions standard local procedure).
14.6 MRC CTU Responsibilities
Medically qualified staff at the MRC CTU and/or the Chief Investigator (or a medically
qualified delegate) will review all SAE reports received. The causality assessment
given by the local Investigator at the hospital cannot be overruled and in the case of
disagreement, both opinions will be provided in any subsequent reports. MRC CTU
staff who are not involved in the day to day running of the trial will be responsible
for unblinding possible SUSARs and notable events for expedited reporting and SARs
for annual reporting. The MRC CTU is undertaking the duties of trial sponsor and is
responsible for the reporting of SUSARs and other SARs to the regulatory authorities
(MHRA and competent authorities of other European member states and any other
countries in which the trial is taking place) and the research ethics committees as
MRC SORCE
SORCE Version 1.2
46
appropriate. The MRC CTU will also keep all investigators informed of any safety
issues that arise during the course of the trial.
MRC SORCE
SORCE Version 1.2
47
Yes
No
Yes
No
Unlikely Not related
Expected
Figure 2.0 Safety Reporting Flowchart
(Pregnancies should be reported on a Pregnancy Form (RE05 Form 14) within one
working day of the investigator becoming aware of the event)
Adverse Event/Adverse Reaction
Was the event serious?
-Resulted in death
-Life-threatening -Required inpatient hospitalisation or prolongation of existing hospitalisation -Persistent or significant disability/incapacity -Congenital anomaly/birth defect
Was the SAE specified in the protocol as being exempt from expedited reporting?
Causal relationship to protocol medication?
Was the SAE one of the recognised undesirable effects of the trial medication?
SUSAR
Record on an SAE form. Notify MRC CTU within
one working day of becoming aware of the
event
SAR Record on an SAE form.
Notify MRC CTU within one working day of
becoming aware of the
event
Unexpected
Exempt SAE Record on the
Treatment Form and send to the MRC CTU
within one month of the CRF due date
AE/AR Record on the
Treatment CRF and
send to the MRC CTU within one month of the CRF due date
SAE
Record on an SAE form. Notify MRC CTU within
one working day of becoming aware of the
event Definitely, Probably, Possibly
CRF: Case report form IB: Investigator’s brochure SAE: Serious adverse event SAR: Serious adverse reaction SPC: Summary of product characteristics SUSAR: Suspected unexpected serious adverse reaction
MRC SORCE
SORCE Version 1.2
48
15.0 Ethical Considerations and Approval
15.1 Ethical Considerations
Following surgery with curative intent, standard of care in primary renal cell
carcinoma is routine clinical examination at appropriate intervals visits only. Patients
in the control arm of a randomised trial would therefore be cared for in this way.
The reason for including a placebo in SORCE is to make the treatments seem as
similar as possible from the patient’s perspective. Importantly, even closer similarity
between the trial arms is achieved by preventing patients and their physicians
knowing which treatment the patient is receiving (so-called ‘double-blinding’). The
double-blind, placebo-controlled approach is generally accepted as the best way to
reduce bias when assessing the effects of new drug treatments in randomised trials.
15.2 Ethical Approval
In the UK, the protocol has main Research Ethics Committee (REC) approval but a
local REC must give favourable SSA before patients are entered at that institution.
For countries outside the UK, approval for the protocol must be obtained for all
participating centres/countries according to local laws and ICH GCP.
Each patient’s consent to participate in the trial should be obtained after a full
explanation has been given of the treatment options, including the conventional and
generally accepted methods of treatment. Patients should receive sufficient time
after being given the trial patient information sheet to consider and discuss
participation in the trial with friends and family. A contact number should be given
to the patient should they wish to discuss any aspect of the trial. Following this, the
principal investigator should determine that the patient is fully informed of the trial
and their participation, in accordance with ICH-GCP guidelines. Patients should
always be asked to sign a consent form. One copy should be given to the patient,
one copy should be kept with patient’s hospital notes, one copy should be kept in the
local investigator’s file and one copy should be sent to the MRC CTU.
The right of the patient to refuse to participate in the trial without giving reasons
must be respected. After the patient has entered the trial, the investigator must
remain free to give alternative treatment to that specified in the protocol, at any
stage, if he/she feels it to be in the best interest of the patient. However, the reason
for doing so should be recorded and the patient will remain within the trial for the
purpose of follow up and data analysis according to the treatment option to which
he/she has been allocated. Similarly, the patient must remain free to withdraw at any
time from the protocol treatment without giving reasons and without prejudicing
his/her further treatment.
A statement of MRC policy on ethical considerations in clinical trials on cancer
therapy, including the question of informed consent, is available from the MRC Head
MRC SORCE
SORCE Version 1.2
49
Office web site (http://www.mrc.ac.uk). This may be used to give guidance to
participating investigators.
15.3 Patient Confidentiality
Patient confidentiality will be respected at all times throughout this trial. On CRFs
and any correspondence, the patient’s trial number, initials and date of birth will be
used as means of identification. However, the patient must be aware that personal
information may be scrutinised during audit by authorised persons but will be treated
as strictly confidential: in this event the anonymity of the patient is guaranteed. The
MRC is registered with the Data Protection Act to hold this information on a
confidential basis (DPA reference number Z5886415). Patients will be followed up in
the long-term through usual mechanisms which may include flagging with the Office
for National Statistics or similar approaches.
MRC SORCE
SORCE Version 1.2
50
16.0 Regulatory approval
Investigators may not enrol patients to this trial without:
• The necessary notification or approval of the protocol and any amendments by
the competent authority of their country (in accordance with local regulations).
• The approval of the protocol and any amendments by their Ethics
Committee/Institutional Review Board (in accordance with local regulations)
17.0 Sponsorship and Indemnity
The sponsor of the trial is the Medical Research Council, as employer of the staff co-
ordinating the trial at the MRC Clinical Trials Unit.
The MRC and NHS are both publicly funded bodies and are not allowed to purchase
advance insurance to cover indemnity because they are backed by the resources of
the Treasury. Cancer Research UK does not provide indemnity cover for participants
in Cancer Research UK funded trials.
The MRC will give sympathetic consideration to claims for non-negligent harm
suffered by a person as a result of a trial or other work supported by the MRC. This
does not extend to liability for non-negligent harm arising from conventional
treatment where this is one arm of a trial.
Where studies are carried out in a hospital, the hospital continues to have a duty of
care to a patient being treated within the hospital, whether or not the patient is
participating in an MRC-supported study. MRC does not accept liability for any
breach in the hospital’s duty of care, or any negligence on the part of employees of
hospitals. This applies whether the hospital is a NHS trust or not.
In addition, Bayer, the company that manufactures and is supplying Sorafenib, is responsible for ensuring that the drug is manufactured in accordance with Good Manufacturing Practice guidelines.
MRC SORCE
SORCE Version 1.2
51
18.0 Ancillary Studies in the UK
18.1 TRANSORCE
The aim of the translational studies (TRANSORCE) is to investigate the mode of
action of sorafenib in RCC and to aid selection of patients most likely to benefit from
sorafenib. This will be done partly by generating tissue microarrays from formalin
fixed embedded sections of primary tissue specimens from consenting patients.
Protein expression will be evaluated using Immunohistochemistry. In addition, VHL
and other relevant genes will be genotyped to identify mutations and single
nucleotide polymorphisms (SNPs) that are present in tumour samples. Further
details regarding the planned translational studies are provided in appendix 5.
18.2 Cost-effectiveness
A major policy issue for the NHS is whether sorafenib represents an efficient use of
resources for patients with RCC. The SORCE trial will, therefore, generate data
which will be used to undertake a thorough economic evaluation of sorafenib. Using
a mixture of CRFs and patient questionnaires, data will be collected on each patient
in the trial on key items of resource use. These will include use of study medication,
in-patient days in hospital (by ward and specialty), out-patient visits and other
cancer treatments. By attaching NHS unit costs to these resource use measures,
per-patient costs and mean costs per study arm will be estimated over the follow-up
of the trial. To contribute to the measurement of the health outcomes associated
with the alternative forms of management, patients will complete the EQ-5D health
status instrument at 3, 6 and 12 weeks, and then 3 monthly until the end of the 3rd
year12.
The EQ-5D assesses five dimensions of health status: mobility, self-care, usual
activities, pain or discomfort, and anxiety or depression (see appendix 4). Each
dimension is measured on a 3-point ordinal scale where a higher score corresponds
to a worse health state (no limitation, some limitation and greatest limitation in
HRQOL). A strength of the EQ-5D is that through their response, patients can
effectively locate themselves into one of 245 possible health states, for which, a
global value (i.e., a “utility score”) is assigned. These utilities form the basis of the
expression of health gain in terms of quality-adjusted life-years (QALYs).13 The utility
score has been previously determined based on the preferences of a sample of 3,395
members of the UK general population.14
To overall purpose of the cost-effectiveness analysis is to establish whether 1-year or
3-year treatment with sorafenib represents a cost-effective use of resources in the
NHS. Resource use and EQ5D data will be brought together with clinical data
collected in the trial including mortality, adverse events and disease progression.
This will be undertaken within a decision analytic model which will also allow relevant
evidence which will facilitate extrapolation of costs and QALYs over the patient’s
lifetime. Modelling of this type will also allow data from sources other than SORCE to
be brought to bear on the evaluation.
MRC SORCE
SORCE Version 1.2
52
19.0 Finance
The SORCE trial will be coordinated at and by the MRC CTU in London. This trial is
funded by Cancer Research UK, MRC and an educational grant from Bayer AG.
Bayer AG are also providing free sorafenib and matching placebo for this study. The
National Cancer Research Network will provide support to individual centres to
facilitate their involvement in NCRN-approved trials. Participating institutions will be
given a per patient payment to cover the cost of additional tests and procedures
associated with the implementation of the trial and management of the patients
enrolled.
20.0 Trial Management and Trial Committees
This trial is being undertaken in accordance with the MRC Guidelines for Good
Clinical Practice in Clinical Trials (1998) and the International Conference on
Harmonisation (ICH) note for Guidance on GCP (ICH, Topic E6, 1995) approved July
17th, 1996. Collaborating investigators should be familiar with these guidelines, which
are available from the MRC Clinical Trials Unit or on the MRC website
(http://www.mrc.ac.uk). Responsibilities of the trial personnel and committees are
as follows:
The Chief Investigator (CI) and the MRC CTU are responsible for the day-to-day
running of the trial as detailed in MRC GCP Guidelines. The MRC CTU will in addition
prepare data reports for the TSC and IDMC, including interim analyses, and will make
safety and progress reports to the main Research Ethics Committee (REC) and
Medicines and Healthcare products Regulatory Agency (MHRA).
The Trial Management Group (TMG) should meet in person at least once every 6
months (but may convene more often or by other means) to advise the CI and MRC
CTU on the promotion and running of the trial. TMG members include active trial
investigators and members with specific interests (e.g. pharmacists, nurses,
radiographers).
The Trial Steering Committee (TSC) is a committee with independent members
and provides overall supervision of the trial. It will meet at least annually and will
receive reports from the MRC CTU, CI and IDMC.
The Independent Data Monitoring Committee (IDMC) group will meet at least
annually, and be provided with interim analysis reports from the MRC CTU, to give
advice on continuing recruitment. A recommendation to discontinue recruitment (in
all patients or in selected subgroups) will be made only if the result is likely to
convince a broad range of investigators including participants in the trial and the
general clinical community. If a decision is made to continue, the IDMC will advise on
the frequency of future reviews of the data on the basis of accrual and event rates.
The IDMC will make recommendations to the TSC as to the continuation of the trial.
MRC SORCE
SORCE Version 1.2
53
Trials
Unit
Trials
Unit
DMC: Data Monitoring Committee
TSC: Trial Steering
Committee
TMG: Trial Management
Group
Participating centres
DMC feedback to TSC & TSC response to DMC
via Trials Unit
DMC feedback to TSC & TSC response to DMC
via Trials Unit
Report from Trials Unit
Question & Feedback
Trial expert panels
Sponsor/Funder
Report from Trials Unit
Question & Feedback
Figure 3: Diagram of relationships between trial committees
21.0 Publication Policy
The results from all institutions will be analysed together and published as soon as
possible. Individual investigators must not publish data concerning their patients that
are directly relevant to questions posed by the trial until the Trial Management Group
(TMG) has published its report. The TMG will form the basis of the Writing
Committee and advise on the nature of publications. Any publication will be sent to
Bayer AG for comment prior to submission. The results of the trial will also be made
available to all patients who took part in the trial. This will usually involve feedback
to the patient by the investigator responsible for their care during the trial.
All publications will include a list of participants, and if there are named authors,
these should include the Chief Investigator(s), Clinical Trial Manager(s) and
Statistician(s) involved in the trial. If there are no named authors then a Writing
Committee will be identified. The trial identification numbers will be attached to all
publications resulting form this trial.
MRC SORCE
SORCE Version 1.2
54
22.0 Protocol Amendments
There are no amendments at present.
MRC SORCE
SORCE Version 1.2
55
23.0 References
1. Wolchock JD, Motzer RJ. Management of renal cell carcinoma. Oncology2000; 14: 29-35 2. Fukata S, Inoue K, Kamada M, Kawada C, Furihata M, Ohtsuki Y, Shuin T. Levels of angiogenesis and expression of angiogenesis-related genes are prognostic for organ-specific metastasis of renal cell carcinoma. Cancer. 2005 Mar 1; 103 (5): 931-42. 3. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA. Sorafenib exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1; 64(19): 7099-109. 4.Sorafenib Investigators brochure. Bayer AG 5. Escudier B, Szczylik C, Eisen T, Stadler WM, Schwartz B, Shan M, Bukowski RM for the TARGET Clinical Trial Group. Randomized Phase III Trial of Sorafenib (BAY 43-9006) – an Oral Multi-Kinase Inhibitor - in Patients with Advanced Renal Cell Carcinoma Presented ASCO 2005. Paper in preparation 6. Eisen T, Escudier B, Szczylik C, Stadler WM, Schwartz B, Shan M, Bukowski RM for the TARGET Clinical Trial Group. Randomized Phase III Trial of Sorafenib (BAY 43-9006) – an Oral Multi-Kinase Inhibitor - in Patients with Advanced Renal Cell Carcinoma Presented ASCO 2006. Paper in preparation
7. Leibovich BC, Blute M, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke, H. Cancer 97, 1663-1671. 8. Royston P & Babiker A. A menu-driven facility for complex sample size calculation in randomized controlled trials with a survival or a binary outcome. Stats Journal 2002; 2:151-163. 9. Peto et al (1976 Peto R, Pike MC, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer (1976) 34, 585)
10. EU directive on clinical trials 2004.
11. MRC Guidelines for Good Clinical Practice in Clinical Trials. Clinical Trials series, MRC, 1998 12. Kind P. The EuroQoL instrument: an index of health-related quality of life. In: Spilker B, editor. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. Philadelphia: Lippincott-Raven, 1996:191-201 13. Drummond MF, Sculpher MJ, Torrance GW, O'Brien B, Stoddart GL. Methods for the Economic Evaluation of Health Care Programmes. 3rd ed. Oxford: Oxford University Press, 2005.
MRC SORCE
SORCE Version 1.2
56
14. Dolan P, Gudex C, Kind P, Williams A. A Social Tariff for EuroQol: Results from a UK General Population Survey. Centre for Health Economics Discussion Paper 138.
Centre for Health Economics, University of York: CHE, 1995 15. DeKernion, J. (1980) Lymphadenectomy for renal cell carcinoma. Therapeutic
implications. Urol. Clin. N. Am. 7(3), 697-703.) 16. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the
response to treatment in solid tumours. J Natl Cancer Inst 2000, 92, 205-216.
17. Gehan EA and Tefft MC. Will there be resistance to the RECIST (Response Evaluation Criteria in Solid Tumours)? J Natl Cancer Inst 2000, 92, 179-181.
MRC SORCE
SORCE Version 1.2
57
24.0 Appendices List of appendices Appendix 1: The Leibovich Risk Model for Prediction of Progression after Radical Nephrectomy for Clear Cell Renal Cell Carcinoma (A) Specimen sampling (B) Sampling frozen material (C) Sampling paraffin sections
(D) TNM Pathological staging Appendix 2: WHO Performance status Appendix 3: (A) Surgery/Nephrectomy Guidelines (B) Line Diagram of Kidney Appendix 4: EQ-5D Questionnaire Appendix 5: TRANSORCE Appendix 6: SmPC for sorafenib Appendix 7: NCI Common Toxicity Criteria (v3.0) Appendix 8: Recist Response Definitions Appendix 9: Patient Information Sheet; Registration in TRANSORCE (V1.1 Feb 07) Appendix 10: Part 1 PIS for the MRC study SORCE (1.2 May 07) Appendix 11: Part 2 PIS for the MRC study SORCE (1.2 May 07) Appendix 12: TRANSORCE Patient Consent Form (V1.1 Feb 07) Appendix 13: SORCE Patient Consent Form (V1.1 Feb 07) Appendix 14: SORCE GP letter (V1.2 May 07) Appendix 15: SORCE trial summary Appendix 16: SORCE Case Report Forms
MRC SORCE
SORCE Version 1.2
58
Appendix 1: The Leibovich Risk Model for Prediction of Progression after Radical Nephrectomy for Clear Cell Renal Cell Carcinoma7
This model is derived from the clinical outcome of 1671 patients with clinically
localized, unilateral clear cell RCC who underwent radical nephrectomy between 1970
and 2000. A large number of clinical and pathological features were assessed.
Metastases-free survival was estimated using the Kaplan-Meier method. A
multivariate Cox proportional hazards regression model was used to determine
associations between the clinical and pathological features and distant metastases.
The median follow-up was 5.4 years. Metastases occurred in 479 patients at a
median of 1.3 years after nephrectomy. Multivariate analysis showed that the
features in the table below were associated with progression to metastases (P <
0.001 for all).
Feature Score
pT1a 0
pT1b 2
pT2 3
Pathological T category of primary tumour (TNM 2002)
pT3a-4 4
pNx or pN0 0 Regional lymph node status (TNM 2002)
pN1 or pN2 2
<10cms 0 Tumour size
10cms or more 1
1 or 2 0
3 1
Nuclear grade
4 3
No 0 Histological tumour necrosis
Yes 1
Application of the scoring system to define risk groups:
Scores Group
0-2 Low risk
3-5 Intermediate risk
6 or more High risk
Pathologists should inspect kidneys removed for cancer and record the following:
• Tumour size; • Direct spread to the adrenal gland or presence of adrenal metastasis; • Invasion into the renal vein or its segmental branches;
MRC SORCE
SORCE Version 1.2
59
Following inspection of the specimen, specific areas for histological examination are
selected to collect clinically relevant data. The following items are required for
calculating the Leibovich score:
• Tumour stage (See Appendix 4 for TNM 2002);
• Regional lymph node status (N category) including number involved relative to total (TNM 2002)
• Maximum diameter of tumour (cm)
• Nuclear Grade (see table 1)
• Histological tumour necrosis (see below)
• Other items that are routinely recorded: Tumour sub-type, Tumour grade, and margin status.
Histological tumour necrosis
Compared with current recommended practice, application of the Leibovich scoring
algorithm only requires one additional item, namely histological tumour necrosis.
Histological tumour necrosis is defined as the presence of any microscopic,
coagulative tumour necrosis and is distinguished from degenerative changes such as
hyalinization, haemorrhage and fibrosis. In addition, the grading system is slightly
different to the most commonly used Fuhrman system, and is therefore given below.
The overall grade is the highest present if it occupies at least one high power field
(0.55mm at x400 magnification). Adequate sampling is essential, taking care to
include all areas with different macroscopic appearances and areas adjacent to foci
of necrosis.
System used to define nuclear grade
Grade Nuclear size and contours
Nucleoli
1 Small, round Inconspicuous, visible only at x400 magnification
2 Round to slightly irregular Mildly enlarged, visible at x200
magnification
3 Round to irregular Prominent, visible at x100
magnification
4 Enlarged, pleomorphic or
giant cells
Microvascular invasion is not part of the algorithm, but has been associated with increased risk. As a potential confounder therefore, it should be recorded.
MRC SORCE
SORCE Version 1.2
60
A Specimen sampling
Preparation
- The following items are required on the day of surgery:
Ice box containing:
10 ml RPMI + protease inhibitor tablet in a universal tube (for tumour tissue) 10 ml RPMI + protease inhibitor tablet in a universal tube (for normal renal)
10 ml RPMI in a universal tube (for tumour primary tissue) IF REQUIRED 10 ml RPMI in a universal tube (for normal renal primary tissue) IFREQUIRED
Transport fluid for tumour Ureter transport fluid in a universal container 50 ml PBS + protease inhibitor tablet in a large falcon
Sucrose solution (4.3g sucrose in 50 ml distilled water) in a large falcon 3 sterile scalpels 3 pairs of sterile forceps
Small dewar containing liquid nitrogen
Dry ice box with 4 embedding chucks placed in the dry ice OCT 2 petri dishes
2 sterile scalpels 2 pairs of sterile forceps
Tissue paper Pieces of foil labelled with tissue number, date and sample type. 4 tumour and 4 normal for OCT embedded blocks (green label)
4 tumour and 4 normal for RNA blocks (red label) 4 tumour and 4 normal for proteomics blocks (blue label) (Allocate the next tissue number from the kidney log)
Kidney dissection
• On receiving a call or bleep from theatre take the ice box across to theatre
• Take the kidney, pathology request card and operation consent form straight to
histopathology to cut up
• If necessary, contact the pathologist to come and dissect the kidney
• Weigh and measure the kidney and note the measurements on the pathology
form
• If the tumour is protruding up to the capsule, ink the surface and rinse with
acetic acid
• Open the kidney using parallel longitudinal incisions to ensure that the formalin
will penetrate the tissue
• Using a sterile scalpel take a sample of the tumour tissue and place into the
universal tubes for tumour tissue. Do not take tissue from any necrotic areas
MRC SORCE
SORCE Version 1.2
61
• Using another sterile scalpel take a sample of normal kidney tissue (cortex &
medulla) and place into the universal tubes for normal renal tissue. Take the
normal tissue from a site far away from the tumour
• Place a sheet of tissue paper soaked in formalin between each slice of the
kidney
• Return the kidney to the specimen pot and cover with formalin
• Make a member of pathology staff aware of the specimen
• Return to the laboratory with the tissue samples
Tissue Dissection
• Pour half of the PBS into the base of a Petri dish
• Using sterile forceps place the tumour sample into the PBS
• Cut the tumour tissue into ~3mm3 blocks and divide into 3 groups for OCT,
RNA and proteomics
• One by one place the RNA pieces briefly on tissue paper to dry off excess
liquid and then wrap in the RNA labelled foil. Immediately drop the samples
into the liquid nitrogen
• Place the OCT pieces briefly on tissue paper and then embed in OCT using
the embedding chucks in the dry ice. Once the OCT has set wrap the
embedded blocks in the OCT labelled foil and drop into the liquid nitrogen
• Pour half of the sucrose solution into the lid of the Petri dish
• Wash the remaining proteomics pieces in the sucrose solution, place briefly
on tissue paper, wrap in the proteomics labelled foil and drop into the liquid
nitrogen
• Repeat for the normal kidney tissue. If present, remove the capsule tissue.
• Only use cortex tissue for the RNA & proteomics blocks. Embed any blocks
containing cortex & medulla in OCT & ensure that they are wrapped in foil
that is labelled as cortex & medulla. Any other OCT blocks can be cortex. Do
not use any blocks that are only medulla
Storage Transfer the kidney samples into the tissue storage liquid nitrogen dewar. Place in a column designated for kidney tissue. Enter the details into the tissue dewar log. B Sampling frozen material This should be selected from viable areas of pure tumour. Normal renal parenchyma is taken from an area furthest from the tumour.
MRC SORCE
SORCE Version 1.2
62
C Sampling paraffin sections
Local protocols should be modified if necessary to ensure that the presence or
absence of relevant features are documented, selecting blocks for maximum efficiency and clearly labeling their site of origin:
• Tumour and perinephric fat (including adrenal if present or circumferential margins if close) for stage and grade
• Tumour and adjacent renal parenchyma for microvascular invasion and grade
• Tumour and renal sinus for stage (peripelvic fat invasion is the same as perinephric fat invasion in the 2002 TNM system), microvascular invasion and grade
• Tumour in renal vein for stage and grade
• Tumour in renal pelvis to document collecting system invasion and grade
• Viable tumour adjacent to necrosis to document necrosis and potential high grade
• Separate nodules in fat to assess nodal status and grade
D TNM Pathological Staging (6th Edition, UICC)
Kidney pT - Primary Tumour pTx Primary tumour cannot be assessed. pT0 No evidence of primary tumour. pT1 Tumours 7 cm or less in greatest dimension, limited to the kidney. pT1a Tumour 4 cm or less. pT1b Tumour more than 4 cm but not more than 7 cm. pT2 Tumour more than 7 cm at greatest dimension, limited to the kidney. pT3 Tumour extends into major veins or directly invades adrenal gland but not
beyond Gerota fascia. pT3a tumour directly invades adrenal gland or perinephric (including renal
sinus) tissues but not beyond Gerota fascia. pT3b Tumour grossly extends into renal vein(s) or vena cava or its wall
below the diaphragm. pT3c Tumour grossly extends into vena cava or its wall above the
diaphragm. pT4 Tumour directly invades beyond Gerota fascia. pN - Regional Lymph Nodes
pNx Regional lymph nodes cannot be assessed. pN0 No regional lymph node metastasis. pN1 Metastasis in a single regional lymph node. pN2 Metastasis in more than one regional lymph node.
MRC SORCE
SORCE Version 1.2
63
Appendix 2: WHO performance status
Clinical Performance Status
0 Able to carry out all normal activity without restriction.
1 Restricted in physically strenuous activity but ambulatory and able to carry
out light work.
2 Ambulatory and capable of all self-care but unable to carry out any work; up
and about more than 50% of waking hours.
3 Capable only of limited self-care; confined to bed or chair more than 50% of
waking hours.
4 Completely disabled; cannot carry out any self-care; totally confined to bed or chair.
MRC SORCE
SORCE Version 1.2
64
Appendix 3: Surgery/Nephrectomy Guidelines
A Aims of Surgery
The aim of the surgery is the removal of the tumour(s) with a surrounding margin of
normal tissue.
Surgery Type and Technique
Excisional surgery for RCC can no longer be described in terms of a “one operation
fits all patients”. The time for a ‘Robson style’ radical nephrectomy for every patient
has passed and the operation is now modified according to the features of the
individual tumour and patient in addition to available resources.
Open and laparoscopic excisional techniques are permissible. Morcellation of the
specimen should be avoided as this may compromise the pathological assessment
and staging.
Considerations during surgery
Lymph nodes
A limited dissection of regional lymph nodes, according to the technique advocated
by deKernion (1980)15., is encouraged but is not mandatory. In this technique,
dissection is limited inferiorly to the origin of the inferior mesenteric artery. The
dissection is taken to the ipsi-lateral side of the junction between the aorta and vena
cava. Superiorly, the dissection extends to the level of the superior aspect of the
adrenal. The inter-aorto-caval, retro-caval and retro-aortic nodes are not excised
unless they contain gross disease. A target of 9 lymph nodes is set. Extended nodal
dissection is not mandatory but can be performed according to surgical preference.
Abnormal lymph nodes (maximum diameter >1cm) seen on pre-operative imaging
should be sampled. Lymph nodes, which appear to contain tumour identified during
surgery, should be excised
Adrenalectomy
Adrenalectomy is encouraged but not mandatory if the tumour is a clinical T3a or higher stage, the tumour has an upper pole location, there are multifocal tumours or there is extension of the primary tumour.
Data Collection following Surgery
Following surgery the surgeon will need to complete surgery form (RE05 Form 4) with details of the procedure. In addition the site of resection of all tumour(s) will be recorded on a line diagram of the kidney (section B continued on next page).
MRC SORCE
SORCE Version 1.2
65
B: Line diagram of the Kidney
Appendix 4: EQ-5D Health Questionnaire
MRC SORCE
SORCE Version 1.2
68
Appendix 5: TRANSORCE
Hypothesis
Inactivating mutations in or methylation of the Von Hippel Lindau (VHL) gene are known to be present in around 70% of clear cell renal carcinomas. This results in upregulation of Hypoxia-Inducible Factor 1 (HIF-1) and consequently in vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) (Kim et al., 2004). This activates VEGFR and PDGFR signalling, drives the development of most clear cell renal cell carcinomas and establishes and maintains angiogenesis. Sorafenib inhibits a number of kinases including VEGFR and PDGFR (Wilhelm et al., 2004). Our hypothesis therefore is that those tumours exhibiting VHL inactivation and elevated VEGFR or PDGFR activity will respond best to adjuvant treatment with sorafenib.
Currently we envisage performing the following analyses in order to investigate the
true mode of action of sorafenib in RCC and to aid selection of patients most likely to
benefit from sorafenib:
It is proposed to analyse tumour tissue and paired tumour-constitutional DNA from a
patients participating in the trial to examine:
1. Relationship between tumour genotypes, expression, and outcome.
2. Relationship between constitutional genotype and outcome.
Lymphocyte DNA will be used as a source of constitutional DNA. Somatic DNA will be
extracted from tumour tissue. Whole genome amplification of extracted tumour DNA
will generate a resource for continuing exploration of markers. Tissue microarrays
(TMA) will be generated from tumours to allow high-throughput
immunohistochemical analyses.
Generation of tissue microarrays and immunohistochemistry
H&E stained sections will be used as templates for marking areas for subsequent
incorporation into a TMA. TMAs containing multiple cores of tumour tissue from
cases will be constructed using a manual tissue arrayer (Beecher Instruments, Silver
Spring, MD). Triplicate cores from each donor block will be randomly distributed
within the TMA to ensure non-biasing of reporting from observer error. Protein
expression will be evaluated using immunohistochemistry based on standard
horseradish peroxidase methodology. Antibodies will be primarily obtained from
commercial sources. Dedicated in-house image analysis software (SPOT
BROWSER®) will be used to capture and store image data prior to analysis.
Molecular analyses
DNA extraction and whole genome amplification: Tumour DNA will be
extracted and purified using Qiagen columns. Where tumour samples are limited whole genome amplification will be used to ensure an adequate DNA resource.
MRC SORCE
SORCE Version 1.2
69
Whole genome amplification of tumour DNA will be undertaken using the GenomiPhi™ system.
Mutation detection: Mutations in VHL, and other relevant genes will be assayed by direct sequencing.
Genotyping: The relationship between constitutional geneotype, as defined by SNP genotype in candidate genes will be assayed by means of TaqMan.
MRC SORCE
SORCE Version 1.2
70
Appendix 6: Summary Products Characteristics (SmPC) for Sorafenib (Nexavar)
1. NAME OF THE MEDICINAL PRODUCT
Nexavar 200 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 200 mg of sorafenib (as tosylate).
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet. Red, round, biconvex film-coated tablets, debossed with Bayer cross on one side and "200"
on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.
4.2 Posology and method of administration Nexavar treatment should be supervised by a physician experienced in the use of anticancer
therapies. The recommended dose of Nexavar in adults is 400 mg (two tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg). It is recommended that sorafenib
should be administered without food or with a low or moderate fat meal. If the patient
intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hour before or 2 hours after the meal. The tablets should be swallowed with a glass of water.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity
occurs.
Posology adjustments:
Management of suspected adverse drug reactions may require temporary interruption or dose reduction of Nexavar therapy. When dose reduction is necessary, the Nexavar dose should be
reduced to two tablets of 200 mg once daily (see section 4.4). Paediatric patients: The safety and efficacy in children and adolescents (< 18 years) have not
been studied. Nexavar is not recommended for use in children and adolescents due to a lack of data on safety and efficacy (see section 5.3).
Elderly patients: No dose adjustment is required in the elderly (patients above 65 years of
age).
Renal impairment: No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance >30 ml/min). No data is available in patients with severe
renal impairment (creatinine clearance <30 ml/min) or in patients requiring dialysis (see section 5.2). Hepatic impairment: No dose adjustment is required in patients with Child Pugh A and B (mild
to moderate) hepatic impairment. No data is available on patients with Child Pugh C (severe)
hepatic impairment (see section 4.4 and 5.2).
4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and precautions for use
MRC SORCE
SORCE Version 1.2
71
Dermatological toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and
rash represent the most common adverse drug reactions with Nexavar. Rash and hand-foot skin reaction are usually CTC (Common Toxicity Criteria) Grade 1 and 2 and generally appear
during the first six weeks of treatment with Nexavar. Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or
dose modification of Nexavar, or in severe or persistent cases, permanent discontinuation of
Nexavar (see section 4.8). Hypertension: An increased incidence of arterial hypertension was observed in Nexavar-treated patients. Hypertension was usually mild to moderate, occurred early in the course of
treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard
medical practice. In cases of severe or persistent hypertension, or hypertensive crisis despite
institution of antihypertensive therapy, permanent discontinuation of Nexavar should be considered (see section 4.8).
Haemorrhage: An increased risk of bleeding may occur following Nexavar administration. If any bleeding event necessitates medical intervention it is recommended that permanent
discontinuation of Nexavar should be considered (see section 4.8). Cardiac ischaemia and/or infarction: In a randomised, placebo-controlled, double-blind study the incidence of treatment-emergent cardiac ischaemia/infarction events was higher in the
Nexavar group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study.
Temporary or permanent discontinuation of Nexavar should be considered in patients who
develop cardiac ischemia and/or infarction (see section 4.8). Hepatic impairment: No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib is mainly eliminated via the hepatic route exposure might be
increased in patients with severe hepatic impairment (see section 4.2 and 5.2).
Warfarin co-administration: Infrequent bleeding events or elevations in the International
Normalised Ratio (INR) have been reported in some patients taking warfarin while on Nexavar therapy. Patients taking concomitant warfarin or phenprocoumon should be
monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes (see
sections 4.5 and 4.8). Wound healing complications: No formal studies of the effect of sorafenib on wound healing have been conducted. Temporary interruption of Nexavar therapy is recommended for
precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical
intervention. Therefore, the decision to resume Nexavar therapy following a major surgical
intervention should be based on clinical judgement of adequate wound healing. Elderly: The experience with the use of Nexavar in elderly patients is limited. Cases of renal failure have been reported. Monitoring of renal function should be considered.
High Risk Patients, according to MSKCC (Memorial Sloan Kettering Cancer Center) prognostic group, were not included in the phase III clinical study and benefit-risk in these patients has
not been evaluated. Drug-drug interactions: Caution is recommended when administering Nexavar with compounds that are
metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways
(see section 4.5). Decreased plasma concentrations of sorafenib cannot be excluded at concomitant administration of anti-acidic medicinal products (see section 4.5).
Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.5).
MRC SORCE
SORCE Version 1.2
72
4.5 Interaction with other medicinal products and other forms of interaction
Anti-acidic drugs: Solubility of sorafenib decreases at increased pH. The effect of anti-acidic medicinal products, such as antacids, H2-antagonists or proton-pump inhibitors, on sorafenib
bioavailability has not been studied. Decreased plasma concentrations of sorafenib cannot be excluded and, if possible, chronic treatment with anti-acidic drugs should be avoided during
treatment with sorafenib.
Inducers of metabolic enzymes: Administration of rifampicin for 5 days before administration
of a single dose of sorafenib resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or glucuronidation (e.g. Hypericum perforatum also known as
St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations.
CYP3A4 inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of
sorafenib. These data suggest that clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely. CYP2C9 substrates: Sorafenib inhibited CYP2C9 in vitro. It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of CYP2C9. The
concomitant treatment with Nexavar and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin or
phenprocoumon should have their INR checked regularly (see section 4.4). CYP2B6 and CYP2C8 substrates: Sorafenib inhibited CYP2B6 and CYP2C8 in vitro, but the
clinical relevance of this inhibition has not been evaluated. It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of
CYP2B6 (e.g. bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone) and CYP2C8 (e.g. paclitaxel,
amodiaquine,
repaglinide). UGT1A1 and UGT1A9 substrates: In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown (see below and section 4.4).
CYP isoforms selective substrates: Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for cytochromes CYP3A4, CYP2D6
and CYP2C19 respectively, did not alter the exposure of these agents. This indicates that
sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes
are unlikely.
In vitro studies of CYP enzyme induction: CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.
P-gp-substrates: In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (Pgp). Increased plasma concentrations of P-gp substrates such as digoxin
cannot be excluded at concomitant treatment with sorafenib. Combination with other anti-neoplastic agents: In clinical studies Nexavar has been administered with a variety of other anti-neoplastic agents at their commonly used dosing
regimens including
gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with Nexavar resulted
in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose
MRC SORCE
SORCE Version 1.2
73
active metabolite SN-38 is further metabolised by the UGT1A1 pathway, there was a 67 -
120% increase in the AUC of SN-38 and a 26 - 42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see section 4.4).
Docetaxel (75 or 100 mg/m2 administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a
21-day cycle with a 3-day break in dosing around administration of docetaxel) resulted in a
36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when sorafenib is coadministered with docetaxel (see section 4.4).
4.6 Pregnancy and lactation
There are no data on the use of sorafenib in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). In rats, sorafenib and its
metabolites were demonstrated to cross the placenta and sorafenib is anticipated to cause
harmful effects on the foetus. Nexavar should not be used during pregnancy unless clearly necessary, after careful consideration of the needs of the mother and the risk to the foetus.
Women of childbearing potential must use effective contraception during treatment. Results from animal studies further indicate that sorafenib can impair male and female fertility (see section 5.3).
It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its
metabolites were excreted in milk. Because sorafenib could harm infant growth and development (see section 5.3), women must not breast-feed during sorafenib treatment.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
There is no evidence that Nexavar affects the ability to drive or to operate machinery.
4.8 Undesirable effects Safety evaluation of Nexavar is based on 1286 cancer patients who received Nexavar in single
agent clinical studies. The most common adverse reactions were diarrhoea, rash, alopecia
and hand-foot skin reaction.
Table 1: Adverse reactions reported in at least 5% of patients in any treatment group – Study 11213 (see Study 1 in section 5.1).
Sorafenib N=451 Placebo N=451
System organ class
Preferred term all grades
grade 3
grade 4
all grades
grade 3
grade 4
Metabolism and Nutrition Disorders
anorexia 9% <1% 0% 5% <1% 0%
Nervous System Disorders
headache 6% 0% 0% 3% 0% 0%
hypertension 12% 2% <1% 1% <1% 0% Vascular Disorders
flushing 6% 0% 0% 2% 0% 0%
diarrhoea 38% 2% 0% 9% <1% 0%
nausea 16% <1% 0% 12% <1% 0%
vomiting 10% <1% 0% 6% <1% 0%
Gastrointestinal Disorders
constipation 6% 0% 0% 3% 0% 0%
MRC SORCE
SORCE Version 1.2
74
rash 28% <1% 0% 9% <1% 0%
alopecia 25% <1% 0% 3% 0% 0%
hand foot syndrome 19% 4% 0% 3% 0% 0%
pruritus 17% <1% 0% 4% 0% 0%
erythema 15% 0% 0% 4% 0% 0%
dry skin 11% 0% 0% 2% 0% 0%
Skin and Subcutaneous
Tissue Disorders
skin exfoliation 7% <1% 0% 2% 0% 0%
arthralgia 6% <1% 0% 3% 0% 0% Musculoskeletal, Connective Tissue
and Bone
Disorders
pain in extremity 6% <1% 0% 2% 0% 0%
fatigue 15% 2% 0% 11% <1% 0% General Disorders
and Administration Site conditions asthenia 9% <1% 0% 4% <1% 0%
Adverse reactions reported in multiple clinical trials are listed below in Table 2, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very common (>1/10),
common (>1/100, <1/10), uncommon (>1/1,000, <1/100).
Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Table 2: All adverse reactions reported in patients in multiple clinical trials
System Organ Class Very Common
> 1/10
Common
>1/100, <1/10
Uncommon
>1/1,000, <1/100
Infections and Infestations
folliculitis
infection
Blood and Lymphatic System Disorders
lymphopenia leucopenia neutropenia
anaemia thrombocytopenia
Immune system Disorders hypersensitivity
reactions (including
skin reactions and urticaria)
Endocrine Disorders hypothyroidism
Metabolism and Nutrition
Disorders
hypophosphataemia anorexia hyponatraemia
dehydration
Psychiatric Disorders depression
Nervous System Disorders peripheral
sensory neuropathy
Reversible posterior
leukoencephalopathy*
Ear and Labyrinth Disorders tinnitus
Cardiac Disorders myocardial ischaemia and infarction*
congestive heart
MRC SORCE
SORCE Version 1.2
75
failure*
Vascular Disorders haemorrhage (inc gastrointestinal*,
respiratory tract* and cerebral
haemorrhage*) hypertension
hypertensive crisis*
Respiratory, Thoracic and
Mediastinal Disorders
hoarseness rhinorrhoea
Gastrointestinal Disorders diarrhoea
nausea vomiting
constipation
stomatitis (including dry
mouth and glossodynia)
dyspepsia
dysphagia
gastro oesophageal
reflux disease pancreatitis
gastritis gastrointestinal
perforations*
Hepatobiliary Disorders increase in bilirubin and jaundice
Skin and Subcutaneous Tissue
Disorders
rash
alopecia hand foot
syndrome**
erythema pruritus
dry skin
dermatitis exfoliative
acne
skin desquamation
eczema
erythema multiforme minor
Musculoskeletal, Connective
Tissue and Bone Disorders
arthralgia
myalgia
Reproductive System and Breast Disorders
erectile dysfunction
gynaecomastia
General Disorders and
Administration Site Conditions
fatigue
pain (including mouth, abdominal,
bone, headache)
asthenia
fever influenza like
illness
Investigations increased amylase
increased lipase
weight decreased
transient increase in transaminases
transient increase in
blood alkaline phosphatase,
INR abnormal, prothrombin level
abnormal
* The adverse reactions may have a life-threatening or fatal outcome.
** palmar plantar erythrodysaesthesia syndrome in MedDRA
Laboratory test abnormalities Increased lipase and amylase were very commonly reported. In Study 1, CTCAE Grade 3 or 4
lipase elevations occurred in 11% of patients in the Nexavar group compared to 7% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1%
of patients in the Nexavar group compared to 3% of patients in the placebo group. Clinical
pancreatitis was reported in 2 of 451 Nexavar treated patients (CTCAE Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group in Study 1.
Hypophosphataemia was a very common laboratory finding, observed in 45% of Nexavar
treated patients compared to 12% of placebo patients. CTCAE Grade 3 hypophosphataemia
(1 – 2 mg/dl) occurred in 13% of Nexavar treated patients and 3% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in
MRC SORCE
SORCE Version 1.2
76
either Nexavar or placebo patients. The aetiology of hypophosphataemia associated with
Nexavar is not known.
CTCAE Grade 3 or 4 was reported for: • lymphopenia in 13% of Nexavar treated patients and 7% of placebo patients,
• neutropenia in 5% of Nexavar treated patients and 2% of placebo patients,
• anaemia in 2% of Nexavar treated patients and 4% of placebo patients, • thrombocytopenia in 1% of Nexavar treated patients and 0% of placebo patients.
4.9 Overdose
There is no specific treatment for Nexavar overdose. The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse events observed at this dose were primarily
diarrhoea and dermatological events. In the event of suspected overdose Nexavar should be
withheld and supportive care instituted where necessary.
5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Protein kinase inhibitors, ATC code: L01XE05
Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and antiangiogenic properties in vitro and in vivo.
Mechanism of action and pharmacodynamic effects
Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice
accompanied by a reduction of tumour angiogenesis. Sorafenib inhibits the activity of targets
present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine
kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.
Clinical efficacy: The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC)
were investigated in two clinical trials:
Study 1 was a Phase III, multi-centre, randomised, double blind, placebo-controlled study in
903 patients. Only patients with clear cell renal carcinoma and low and intermediate risk MSKCC
(Memorial Sloan Kettering Cancer Center) were included. The primary endpoints were overall survival and progression-free survival (PFS).
Approximately half of the patients had an ECOG performance status of 0, and half of the patients were in the low risk MSKCC prognostic group.
PFS was evaluated by blinded independent radiological review using RECIST criteria. The PFS
analysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patients randomised to Nexavar compared to 84 days for placebo patients (HR =0.44; 95% CI: 0.35-0.55; p<0.000001). Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the treatment effect size.
An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903 patients. The nominal alpha value for this analysis was 0.0094. The median survival
was 19.3 months for patients randomised to Nexavar compared to 15.9 months for placebo patients (HR =0.77; 95% CI: 0.63-0.95; p=0.015). At the time of this analysis, about 200
patients had crossed-over to sorafenib from the placebo group.
Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies,
including RCC. Patients with stable disease on therapy with Nexavar were randomised to placebo or continued Nexavar therapy. Progression-free survival in patients with RCC was
MRC SORCE
SORCE Version 1.2
77
significantly longer in the Nexavar group (163 days) than in the placebo group (41 days)
(p=0.0001, HR=0.29).
5.2 Pharmacokinetic properties Absorption and distribution:
After administration of Nexavar tablets the mean relative bioavailability is 38 - 49% when
compared to an oral solution. The absolute bioavailability is not known. Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours. When
given with a high-fat meal sorafenib absorption was reduced by 30% compared to administration in the fasted state.
Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins is 99.5%.
Multiple dosing of Nexavar for 7 days resulted in a 2.5- to 7-fold accumulation compared to
single dose administration. Steady state plasma sorafenib concentrations are achieved within 7 days, with a peak to trough ratio of mean concentrations of less than 2.
Metabolism and elimination: The elimination half-life of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised
primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the
circulating analytes in plasma at steady state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of
sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in faeces, and 19% of
the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in faeces but not in urine, indicating that biliary excretion of
unchanged drug might contribute to the elimination of sorafenib.
Pharmacokinetics in special populations: Analyses of demographic data suggest that there is
no relationship between pharmacokinetics and age (up to 65 years) gender or body weight. Paediatric Population: No studies have been conducted to investigate the pharmacokinetics of
sorafenib in paediatric patients. Race: The mean sorafenib exposure was lower in Japanese patients than in Caucasian patients, but the exposure was highly variable. The clinical relevance of this observation is
unknown. Renal impairment: In four Phase I clinical trials, steady state exposure to sorafenib was
similar in patients with mild or moderate renal impairment compared to the exposures in
patients with normal renal function. No data is available for patients with severe renal impairment (creatinine clearance <30 ml/min). Hepatic impairment: In hepatocellular carcinoma patients with mild or moderate hepatic
impairment, exposure values were comparable and within the range of exposures observed in
patients without hepatic impairment. There are no data for patients with Child Pugh C (severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might
be increased in this patient population.
5.3 Preclinical safety data The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).
MRC SORCE
SORCE Version 1.2
78
After repeated dosing to young and growing dogs effects on bone and teeth were observed
at exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral growth plate, hypocellularity of the bone marrow next to the altered growth plate
and alterations of the dentin composition. Similar effects were not induced in adult dogs.
The standard program of genotoxicity studies was conducted and positive results were
obtained as an increase in structural chromosomal aberrations in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity in the presence of metabolic activation was
seen. Sorafenib was not genotoxic in the Ames test or in the in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug
substance (< 0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Furthermore, the sorafenib batch tested in the standard genotoxicity battery included
0.34% PAPE.
Carcinogenicity studies have not been conducted with sorafenib.
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. An adverse effect on male and female fertility can however be expected because repeat-dose studies in animals have shown changes in male and female reproductive organs
at exposures below the anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate, and
seminal vesicles of rats. Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular degeneration in the
testes and oligospermia.
Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and
rabbits at exposures below the clinical exposure. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an
increased number of external and visceral malformations.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients Core:
croscarmellose sodium microcrystalline cellulose
hypromellose
sodium laurilsulfate magnesium stearate
Coating:
hypromellose macrogol (3350)
titanium dioxide (E 171)
ferric oxide red (E 172) 6.2 Incompatibilities Not applicable.
6.3 Shelf life 30 months.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
112 (4 x 28) tablets in transparent (PP/Aluminium) blister packs.
6.6 Special precautions for disposal and other handling
MRC SORCE
SORCE Version 1.2
79
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Bayer HealthCare AG D-51368 Leverkusen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/06/342/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION July 2006
10. DATE OF REVISION OF THE TEXT January 2007
MRC SORCE
SORCE Version 1.2
80
Appendix 7 – NCI Common Toxicity Criteria (v3.0) The following are some expected toxicities. For full list see:
http://ctep.cancer.gov/reporting/ctc.html
Grade 1 2 3 4 5
Mild Moderate Severe Life threatening
Death
Cardiac General
Hypertension Asymptomatic, transient (<24
hrs) increase by >20 mmHg (diastolic) or to > 150/100 if previously WNL; intervention not indicated
Recurrent or persistent (≥24 hrs) or
symptomatic increase by >20 mmHg (diastolic) or to >150/100 if previously WNL; monotherapy may be indicated
Requiring more than one drug or more intensive
therapy than previously
Life-threatening
consequences (e.g., hypertensive crisis)
Death
Constitutional Symptoms
Fatigue (asthenia, lethargy, malaise)
Mild fatigue over baseline
Moderate or causing difficulty performing some ADL
Severe fatigue interfering with ADL
Disabling -
Dermatological /skin
Alopecia Thinning or patchy
Complete - - -
Hand-foot syndrome
Minimal skin changes or dermatitis (e.g., erythema) without pain
Skin changes (e.g., peeling, blisters, bleeding, edema) or pain, not interfering with function
Ulcerative dermatitis or skin changes with pain interfering with function
- -
Rash /desquamation
Macular or popular eruption or erythema without associated
symptoms
Macular or popular eruption or erythema with pruritis or other associated symptoms; localised
desquamation or other lesions covering <50% of BSA
Severed, generalised erythroderma or macular popular or vesicular eruption, desquamation covering >50% BSA
Generalised exfoliative, ulcerative, or bullous dermatitis
Death
Gastrointestinal
Diarrhoea Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline
Increase of 4-6 stools per day over baseline; IV fluids indicated <24hrs; moderate increase in ostomy output compared to baseline; not interfering with ADL
Increase of ≥ 7 stools per day over baseline; incontinence; IV fluids indicated ≥ 24hrs; hospitilisation; severe increase in ostomy output compared to baseline; interfering with ADL
Life-threatening consequences (e.g. haemodyamic collapse)
Death
Nausea Loss of appetite without alteration in
eating habits
Oral intake decreased without significant weight loss,
dehydration or malnutrition; IV fluids indicated <24 hrs
Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN
indicated ≥ 24 hrs
Life-threatening consequences
Death
Vomiting 1 episode in 24 hrs
2-5 episodes in 24 hrs; IV fluids indicated <24 hrs
≥6 episodes in 24hrs; IV fluids, or TPN indicated ≥24 hrs
Life-threatening consequences
Death
Pain
Pain Mild pain not interfering with function
Moderate pain; pain or analgesics interfering with function, but not
interfering with ADL
Severe pain; pain or analgesics severely interfering with ADL
Disabling -
MRC SORCE
SORCE Version 1.2
81
Appendix 8 – RECIST response definitions
o RECIST (Response Evaluation Criteria In Solid Tumours) has now
superseded the old WHO response criteria for solid tumours16,17
o The key differences are:
• instead of measuring lesions in 2 dimensions it is now only necessary
to measure the longest diameter
• disease is classified as measurable or not measurable but the term
evaluable is no longer used
Measurable disease:
o Disease is measurable if there is at least one measurable target lesion.
Target lesions should be selected on the basis of size and suitability for
repeat measurement, up to a maximum of 5 measurable lesions per
organ, and up to a maximum of 10 lesions in total. These should be
representative of all involved organs
o Target lesion must be accurately measurable in at least 1 dimension, with
the longest diameter ≥20 mm (or ≥10 mm with spiral CT scan). If the
lesion is smaller than this then it is classed as non-measurable
o Measurements must be taken as close as possible to the beginning of
treatment and never more than 4 weeks before the start of treatment.
Target lesions should be assessed by CT, MRI or CXR, not by clinical
assessment alone. The same imaging modality should be used throughout
for any given patient
• When intra-venous contrast agents are given with CT, it is important
to measure hepatic lesions in the same vascular phase on
subsequent examinations
• If MRI is used than the same sequence (e.g. T1 or T2 weighted
images) in the same anatomical plane should be used
o Add the longest diameters of the target lesions and report this as the
baseline sum longest diameter. This will be used as a reference by
which the tumour response will be measured
Response definitions:
o Complete response (CR): disappearance of all lesions (i.e. all evidence
of disease, not just the target lesions) determined by 2 observations not
less than 4 weeks apart.
o Partial response (PR): ≥30% decrease in the sum of longest diameters
of target lesions compared to baseline, with response or stable disease
observed in non-target lesions, and no new lesions.
o Stable disease (SD): neither sufficient shrinkage to qualify for response
or sufficient increase to qualify for progressive disease in target lesions,
MRC SORCE
SORCE Version 1.2
82
with response or stable disease observed in non-target lesions, and no
new lesions
o Progressive disease (PD): ≥20% increase in the sum of longest
diameters of target lesions compared to smallest sum longest diameter
recorded, or unequivocal progression of non-target lesions, or appearance
of new lesions.
Reminder:
o Response is judged against baseline, but progression is judged against
the smallest recorded score.
Example:
Month 0 3 6 9 12
Measurement (mm) 100 90 50 55 ≥60
Classification Baseline SD PR PR PD
MRC SORCE
SORCE Version 1.2
83
Appendix 9: Patient Information Sheet - Enrolment in TRANSORCE
Version 1.1 February 2007
1. Title: Collection of pathology and blood samples for use in kidney
cancer research
2. Invitation
You are being invited to take part in a research study. Before you decide it is
important for you to understand why the research is being done and what it will
involve. Please take time to read the following information carefully. Talk to others
about the study if you wish. Ask if there is anything that is not clear or if you would
like more information. Take time to decide whether or not you wish to take part.
Thank you for reading this.
3. What is the purpose of the study?
The purpose of this study is to collect blood and surplus pathology samples from
people with suspected or confirmed renal cell cancer. The samples will later be
tested to find out if they contain any genetic or other abnormalities that may cause
kidney cancer or affect the way the cancer responds to treatment
You may be asked to participate at one of two stages:
1. Prior to an operation to remove a suspected kidney cancer
2. After an operation to remove a kidney cancer.
If you have already had your surgery, and have been diagnosed as having a kidney
cancer that has an intermediate or high risk of returning we will also ask you to
consider taking part in another part of this study which is trying to find out the best
way of treating kidney cancer like yours. If you are eligible for this part of the study
your doctor will give you information about it.
MRC SORCE
SORCE Version 1.2
84
4. Why have I been chosen?
When patients have surgery, samples from their cancer are often saved, as a
routine, in the hospital pathology laboratory. Since you are about to have or have
recently had surgery we would like to request your permission to use these samples
in future scientific studies. We would also like your permission to take a 20ml blood
sample for use in these studies.
We will be asking around 300 patients each year to participate in this part of the
study.
5. Do I have to take part?
No. It is up to you to decide whether or not to take part. If you do decide to take
part you will be given this information sheet to keep and be asked to sign a consent
form. If you decide to take part you are still free to withdraw at any time and
without giving a reason. A decision to withdraw at any time, or a decision not to
take part, will not affect the standard of care you receive.
6. What will happen to me if I take part?
The samples removed from your kidney cancer and normal kidney tissue and the
blood sample will be tested for genetic and other abnormalities. All work carried out
on the samples will have been previously approved by an ethics committee.
You are free to withhold permission without affecting your future treatment or your
relationship with your doctor.
All research carried out on the samples will be coded: a code number, not your
name, will identify your specimens and neither you nor your relatives will be
identified or contacted.
Any results from the studies carried out on your samples will only be available
several years after your operation and so will not affect your future treatment.
However, the research may inform future testing programs that would then be
available later through the NHS and so be of benefit to many patients with kidney
cancer in the future.
MRC SORCE
SORCE Version 1.2
85
Please note that if any inventions resulting in commercial gain emerge from any of
the above research, you will not be eligible to benefit financially from these
discoveries.
7. What are the possible disadvantages and risks of taking part?
Participation in this study may not require any extra tests or procedures that you
would not routinely have, as the blood sample may be taken during routine care. If
not taken during routine care you will have one extra blood sample taken. Tissue
samples are routinely taken during surgery and their removal will not impact on your
wellbeing.
However, if you have private medical insurance you should check that participating in
this study does not affect your policy in any way.
8. What are the possible benefits of taking part?
Whether or not you choose to give consent for samples to be used in this research
study you will still receive the same standard of care. If you do decide to participate
we hope that the knowledge gained from your participation may benefit other
patients with kidney cancer in the future.
9. What if something goes wrong?
In the event that something does go wrong and you are harmed during this study
there are no special compensation arrangements. If you are harmed and this is due
to someone’s negligence then you may have grounds for a legal action for
compensation but you may have to pay your legal costs.
If you have a concern about any aspect of the way you have been approached or
treated during the course of this study, you should speak with your doctor. If you
remain unhappy or would rather complain formally, you can do this through the NHS
Complaints Procedure. Participation in this study does not affect your normal rights
to complain about any aspect of your treatment and care. (Contact number Details
can be obtained from the hospital.)
The Medical Research Council (MRC) who are responsible for this study will give
sympathetic consideration to claims for non-negligent harm suffered by a person as a
MRC SORCE
SORCE Version 1.2
86
result of a trial or other work supported by MRC. MRC acts as its own insurer and
does not provide cover for non-negligent harm in advance for participants in MRC-
funded studies.
Where studies are carried out in a hospital, the hospital continues to have a duty of
care to a patient being treated within the hospital, whether or not the patient is
participating in an MRC-supported study. MRC does not accept liability for any breach
in the hospital’s duty of care, or any negligence on the part of employees of
hospitals. This applies whether the hospital is a NHS Trust or not.
10. Will my taking part in this study be kept confidential?
If you agree to take part in this study the MRC Clinical Trials Unit will collect the
following information about you; your name, date of birth and NHS number, and
then allocate you a unique number within the study. All of your personal details will
be kept confidential. Your samples will be held at the Royal Marsden in Surrey and
will only be identified by the unique number provided by the MRC.
We will also attempt to get some details about the surgery you have had or will
receive to remove your kidney cancer and some details about cancer that was
removed. This information will also only be identified by the unique number
provided by the MRC.
We would also like to flag your records with the Office of National Statistics or trace
them via the NHS Central Register or equivalent so that if you move away or decide
not to continue with the study we will still be able to find out how you are doing.
You will be asked a question about this on the consent form that you will have to
sign before you are entered into the study.
11. What will happen to the results of the research study?
After completion of the study the results will be presented at national/international
scientific meetings and published in a leading medical journal. At no point in the
analysis or publication will any information about the identity of individual patients be
revealed. A copy of the results will be circulated to your doctor and will also be
available to you or your family on request.
MRC SORCE
SORCE Version 1.2
87
12. Who is organising and funding the research?
The study is being sponsored by the Medical Research Council (MRC), which
undertakes public sector research. The study is being organised by the MRC Clinical
Trials Unit, based in London and has been funded by CTAAC and TRICC (Cancer
Research UK funding committees) and the MRC CTU.
13. Who has reviewed the study?
As well as a review by the funding bodies listed above, the study has been reviewed
and approved by the National Cancer Research Institute (NCRI) Kidney Clinical
Studies Group. All studies carried out on your samples will also be approved by a
Research Ethics Committee.
14. Contacts for Further Information
If you have any further questions about your illness or this research study, please
discuss them with your doctor.
Give details here:
Contact names and telephone numbers: ....................................................................................................................................................
....................................................................................................................................................
You may also find it helpful to contact:
CancerBACUP, an independent patient advisory group (Freephone: 0808 800 1234;
http://www.cancerbacup.org.uk/Home)
Cancer Research UK website http://www.cancerhelp.org.uk
Consumers for Ethics in Research website http://www.ceres.org.uk/index.html
Thank you for taking the time to read this information and for considering taking part
in this study.
MRC SORCE
SORCE Version 1.2
88
Appendix 10: Patient Information Sheet for the MRC study SORCE
Version 1.2 May 2007
Part 1.
1. Study Title
A Phase III Study Comparing Sorafenib with Placebo in Patients who have
had a kidney cancer removed (SORCE)
2. Invitation
You are being invited to take part in a research study. Before you decide it is
important for you to understand why the research is being done and what it will
involve. Please take time to read the following information carefully. Talk to others
about the study if you wish.
• Part 1 tells you the purpose of this study and what will happen to you if you take
part.
• Part 2 gives you more detailed information about the conduct of the study.
Please ask if there is anything that is not clear or if you would like more information.
Take time to decide whether or not you wish to take part.
Thank you for reading this.
3. What is the purpose of the study?
Removing a kidney or part of a kidney, by a surgical operation is usually the best
treatment if you have kidney cancer. Unfortunately, there is still a risk that your
cancer could return. This is because a few cancer cells may already have escaped
from your kidney into another part of your body. Sometimes your own immune
system will kill off these last few cells, but sometimes they can grow back. We would
like to find ways to stop this happening.
This study, also called a clinical trial, is designed to discover whether taking a drug
called sorafenib after the operation can reduce the risk of kidney cancer returning.
We would also like to know how long treatment with sorafenib should continue. We
hope that if sorafenib reduces the risk of kidney cancer returning that it will also help
MRC SORCE
SORCE Version 1.2
89
patients live longer. Sorafenib may prevent tumour cells from growing and
spreading, for example, by preventing the development of new blood vessels.
Sorafenib has recently been used in a large study of patients with advanced kidney
cancer (cancer that has spread to other parts of the body). In that study, treatment
with sorafenib resulted in 70% of patients’ kidney cancers shrinking or not increasing
in size. These results compare well with those from the standard approaches to
treating advanced kidney cancer. Compared with the standard treatments for
advanced kidney cancer patients treated with sorafenib tolerated treatment very well
and had much fewer side effects. Sorafenib is therefore an ideal drug to test for
patients like you, with newly diagnosed kidney cancer that has not spread to other
parts of the body, as we hope that it will prevent or delay the chances of your kidney
cancer returning.
The standard treatment after surgery at the moment is ‘active surveillance. This
means no treatment, but having regular checks so that if the cancer does come back
it is caught early. The treatments you might receive in this study are described in
section 6 below.
4. Why have I been chosen?
You have recently had surgery to remove your kidney cancer. The doctors treating
you have now had a chance to look at the tumour that was removed and they think
that there is a risk that your tumour might return.
Over the next 5 years we will invite 1656 patients like you, from both the UK and
elsewhere, to take part in this study. In order to be eligible for the study your
treatment must start within 3 months of the date when you had surgery.
5. Do I have to take part?
No. It is up to you to decide whether or not to take part. If you do decide to take
part you will be given this information sheet to keep and be asked to read and sign a
consent form. If you decide to take part you are still free to withdraw at any time
and without giving a reason. A decision to withdraw at any time, or a decision not to
take part, will not affect the standard of care you receive.
MRC SORCE
SORCE Version 1.2
90
6. What will happen to me if I take part?
This study is designed as a “randomised”, “double-blind”, “placebo-controlled” clinical
trial.
Once you have agreed to enter the trial, you will be randomised to a course of
treatment. This means that a computer will randomly allocate patients to treatment
groups in the trial. This is done so that each group has a similar mix of patients. If
at the end of the trial there are any differences between how the different groups
do, we can reliably say that it is due to the treatment.
“Double-blind” means that neither you nor your doctor will know in which treatment
group you are. If your doctor needs to find out which treatment you are receiving
he/she can do so. A “placebo” is a “dummy treatment”, which looks like the genuine
medicine but contains no active ingredient. In a double-blind, placebo-controlled
study both the real drug and the placebo are packaged in such a way that neither
you nor your doctor can tell which is which. We are using a placebo in this trial so
that we can make as fair an assessment as possible about the effects of the
sorafenib treatment. No standard treatment is withheld from you if you are on
placebo or sorafenib.
The treatment arms in this study are:
1. Placebo only for 3 years
2. Sorafenib for 1 year followed by placebo for 2 years
3. Sorafenib only for 3 years
For every 8 patients entered into the study, 2 will receive placebo for 3 years, 3
patients will receive sorafenib for one year followed by placebo for 2 years and 3 will
receive sorafenib for 3 years.
• Screening period (checks to make sure you are eligible for the study) – up to
3 months
• Treatment (taking tablets) period – up to 3 years
• Follow-up period (follow-up visits to the hospital) – 6 monthly during years 4
and 5 and annually thereafter.
MRC SORCE
SORCE Version 1.2
91
Screening: After your surgery you will have blood tests and a CT scan. As well as
telling your doctor about your state of health after the operation, the results of these
tests will also confirm whether you are suitable for entry into the study.
Treatment Period (Years 1, 2 & 3): In the study you will be asked to take two
tablets twice a day for 3 years. You will see your doctor every 3 months during this
period. You will have some blood tests, x-rays and CT scans to check that your
kidney cancer has not returned and that there are no problems with your treatment.
Sometimes it may be necessary to see your doctor more frequently. If you are
having any problems with your treatment then your doctor may need to interrupt
your treatment or to reduce the number of tablets you are taking.
Follow-up (Years 4-8): You will no longer have to take any trial treatment. Your
doctor will continue to see you every 6 months to check that your kidney cancer has
not returned. Sometimes your doctor may need to see you more frequently.
To summarise, your participation in this study will help determine the following:
• Whether sorafenib reduces the risk of kidney cancer returning,
• Whether sorafenib increases the length of survival for patients with kidney
cancer,
• Whether sorafenib has any side effect on patients who take the drug for up
to 3 years,
• If sorafenib reduces the risk of kidney cancer, whether it is best to give it for
1 year or 3 years,
• If tests can be developed to help predict which patients benefit most from
sorafenib.
7. What do I have to do?
You must tell your doctor and/or research staff about all past and present diseases
and allergies of which you are aware and all drugs and medications which you are
presently using.
Whilst taking part in the study, it is important that you take your tablets as instructed
- two tablets morning and evening continuously. If you miss a dose, do not take a
double dose on the next occasion, just let your doctor or research nurse know the
MRC SORCE
SORCE Version 1.2
92
next time you see them. It is also important that you take reduced doses when
instructed to do so by your doctor.
It is also important that you attend all appointments either at your GP or at the
hospital that your study doctor asks you to. You should be offered assistance to
cover the cost of the extra visits to hospital as a result of your participation in this
study. These extra visits are at 1, 2, 3, 4, 5 and 6 weeks. All other visits would be
made as part of routine care outside of the study.
The table below shows a summary of visits.
Tests Assessment time points How much is extra
History
At baseline Standard*
Observed/Expected Toxicities
At baseline, 3 weeks, 6 weeks, 3 months, then 3-monthly until the third year in the study, then 6-monthly until end of fifth year in the study, then annually thereafter
Clinic visits at 3 & 6 weeks
Blood pressure monitoring Weekly for all patients during the first 6 weeks after randomisation; weekly during the first 6 weeks of treatment with open-label sorafenib
All extra
Blood parameters
At 3 weeks, 6 weeks, 3 months, then 3-monthly until the third year in the study then annually thereafter
Normally done only annually. The rest are extra, however you will be visiting the hospital 3-monthly for other routine checks
CT scans of the chest, abdomen and pelvis
At baseline Standard*
CT scans of the chest and abdomen
6 monthly during the first 3 years of the study
Standard*
Chest x-rays At 3 months from baseline and then 6 monthly in years 1-5, and annually
thereafter.
Standard*
*These tests are considered standard by the international panel of experts who designed
this study and by most UK centres. However, it is possible that your centre routinely carries out these tests either more or less frequently. If SORCE will involve more or less
tests than you would normally receive your doctor or research nurse will make you aware of this.
MRC SORCE
SORCE Version 1.2
93
This study requires you to undergo a series of CT and x-ray examinations to follow
the progress of your treatment. You will only receive the same examinations as you
would if you did not agree to participate in this study. The x-ray dose arising from
these examinations may rise to the equivalent of several 10’s of year’s natural
background radiation. The Health Protection Agency Radiation Protection Division
describes ‘a few years’ natural background radiation as ‘Low Risk’. The risks from
these examinations would have to be described as ‘Moderate Risk’ in normal healthy
subjects. However, in your case, the x-ray examinations are unlikely to result in any
additional radiation risk arising from this study and you are unlikely to notice any
health detriment arising from it.
If you feel the need to take other medications, including over-the-counter
medications or alternative therapies, please talk with your GP or study doctor before
you take them.
You should report any side effects to your study doctor who usually can prescribe
medicines to help control them.
If you decide to take part you will be given a small card that you can carry around
with you. This card will include the contact details for your study doctor and study
nurse.
8. What is the drug that is being tested?
The drug being tested in this clinical trial is called sorafenib. This drug has been
tested in humans with several different types of cancer and early results show that
tumours get smaller in approximately 70% of patients with advanced kidney cancer.
It is licensed for patients with advanced kidney cancer (this means that the cancer
has spread to other parts of the body). Sorafenib is not currently licensed for the
treatment of kidney cancer that has been removed, and has not spread to other
parts of the body. It is known as a “targeted therapy”.
9. What are the alternatives for diagnosis or treatment?
At the moment the standard treatment after surgery to remove kidney cancer is
active surveillance. This means having regular checks so that if the cancer does
come back it is caught early.
MRC SORCE
SORCE Version 1.2
94
10. What are the side effects of any treatment received when taking
part?
Treatments often have side effects. The treatments used during the course of this
study may cause some side effects. If you have any adverse symptoms, you must
report them to your doctor.
Most side effects that have been reported in trials using sorafenib have been mild.
However, it is possible that other potential side effects may become apparent or
more severe side effects are observed, as more patients receive Sorafenib.
The most common side effects of sorafenib treatment seen so far include:
• fatigue
• rash
• redness and peeling of the hands and feet
• diarrhoea
• hair loss
• loss of or poor appetite
• weight loss
Although infrequent, some patients have had redness and peeling of the hands and
feet severe enough to cause blistering and pain. Having a short break from taking
the study drug was necessary and these patients recovered fully.
Less frequently reported side effects of sorafenib include: abnormalities in liver
function tests, inflammation of the pancreas, nausea, vomiting and pain. In addition,
several cases of increase in blood pressure, dehydration and bleeding have been
reported. However, whether sorafenib caused these problems is not clear.
If you become concerned about any side-effects at any stage during your treatment
please contact: <Add site-specific contact details>
11. What are the possible disadvantages and risks of taking part?
The taking of blood samples from a vein for the blood tests may cause pain or
bruising. Skin or vein irritation, blood-clot formation, bleeding at the injection site, or
infection could also occur.
MRC SORCE
SORCE Version 1.2
95
The treatment being tested in this study may include unknown risks to an unborn
child; therefore pregnant or breast-feeding women will be excluded from this study.
A pregnancy test will be performed on all women of childbearing potential at the
start of the study. Both male and female patients who are fertile will need to use a
medically approved method of contraception. If you are a female patient and you
think you have become pregnant, or you are male and your partner thinks they have
become pregnant, whilst you are participating in the study you must tell your study
doctor immediately. Your study doctor should inform your General Practitioner.
Female patients will be withdrawn from the study immediately. Your study doctor will
discuss the options for male patients.
If you have private medical insurance you should check that participating in this
study does not affect your policy in any way.
12. What are the possible benefits of taking part?
Some doctors have already used sorafenib to treat patients whose kidney cancer has
re-grown after surgery, and some patients have had good responses. That is why we
think it may help to stop the cancer returning in the first place.
However, because it is not possible to predict how an individual person will react to
any drug, there is a chance that you will receive no direct benefit from being in this
study. We hope that the knowledge gained from your participation may however
benefit other patients with kidney cancer in the future.
MRC SORCE
SORCE Version 1.2
96
13. What happens when the research study stops?
If your kidney cancer does return while you are receiving treatment on the study
then your doctor will find out which treatment you had been taking. If you were
taking placebo then your doctor may offer you sorafenib to treat your kidney cancer.
14. What if there is a problem?
Any complaint about the way you have been dealt with during the study or any
possible harm you might suffer will be addressed. The detailed information on this is
given in Part 2.
<Add site-specific contact details in case the patient has a complaint.>
15. Will my taking part in this study be kept confidential?
Yes. All the information about your participation in this study will be kept
confidential. The details are included in Part 2.
16. Contact Details:
<Please provide the patient with contact information including the name of their
treating physician and a 24 hour telephone contact number>
This completes part 1 of the Information Sheet.
If the information in Part 1 has interested you and you are considering
participation, please continue to read the additional information in Part 2
before making any decision.
MRC SORCE
SORCE Version 1.2
97
Appendix 11: Patient Information Sheet for the MRC study SORCE
Version 1.2 May 2007
Part 2.
1. Study Title
A Phase III Study Comparing Sorafenib with Placebo in Patients who have
had a kidney cancer removed (SORCE)
2. What if relevant new information becomes available?
Sometimes during the course of a research project, new information becomes
available about the treatment that is being studied. If this happens, your doctor will
tell you about it and discuss with you whether you want to continue in the study. If
you decide to stop treatment your doctor will make arrangements for your care to
continue. If you decide to continue in the study you will be asked to sign an updated
consent form.
Also, on receiving new information your doctor might consider it to be in your best
interests to withdraw you from the study/trial treatment. He/she will explain the
reasons and arrange for your care to continue.
If the study is stopped for any other reason, you will be told why and your
continuing care will be arranged.
3. What will happen if I don’t want to carry on with the study?
You can decide that you no longer wish to receive study treatment at any time. We
would however like you to keep in contact with your doctor so that we can continue
to receive information about your progress. If you do not wish us to have access to
further information about your progress please inform your doctor. If you stop study
treatment your doctor will continue to provide you with the best available care.
MRC SORCE
SORCE Version 1.2
98
4. What if there is a problem?
In the event that something does go wrong and you are harmed during this study
there are no special compensation arrangements, other than the following standard
arrangements for trials sponsored by the MRC:
� If you are harmed and this is due to someone’s negligence then you may have
grounds for a legal action for compensation but you may have to pay your legal
costs.
� If you have a concern about any aspect of the way you have been approached or
treated during the course of this study, you should speak with your doctor. If
you remain unhappy or would rather complain formally, you can do this through
the NHS Complaints Procedure. Participation in this study does not affect your
normal rights to complain about any aspect of your treatment and care. (Contact
number Details can be obtained from the hospital.)
� The MRC will give sympathetic consideration to claims for non-negligent harm
suffered by a person as a result of a trial or other work supported by MRC. This
does not extend to liability for non-negligent harm arising from conventional
treatment where this is one arm of a trial. MRC acts as its own insurer and does
not provide cover for non-negligent harm in advance for participants in MRC-
funded studies.
� Where studies are carried out in a hospital, the hospital continues to have a duty
of care to a patient being treated within the hospital, whether or not the patient
is participating in an MRC-supported study. MRC does not accept liability for any
breach in the hospital’s duty of care, or any negligence on the part of employees
of hospitals. This applies whether the hospital is a NHS Trust or not.
� In addition, Bayer, the company that manufactures and is supplying Sorafenib, is
responsible for ensuring that the drug is manufactured in accordance with
international standards for drug manufacture.
5. Will my taking part in this study be kept confidential?
If you decide to participate in this trial, the Medical Research Council (MRC) Clinical
Trials Unit will collect relevant information, about you. All of the information
collected about you during the course of the research will be kept strictly
confidential. All procedures for handling, processing, storage and destruction of your
data are compliant with the Data Protection Act 1998. No individual patients will be
identified when the results of the trial are published.
MRC SORCE
SORCE Version 1.2
99
If you agree to join the study, some parts of your medical records and the data
collected for the study will be looked at by authorised persons from the MRC. They
may also be looked at by people from the company that makes sorafenib (Bayer is
the name of the company) and by representatives from the regulatory authorities to
check that the study is being carried out correctly.
Your GP will be informed of your participation in the trial, but otherwise all
information about you and your treatment will remain strictly confidential
We will ask if we can flag your records with the Office of National Statistics or trace
them via the NHS Central Register so that if you move away or decide not to
continue with the trial we will still be able to find out how you are doing. You will be
asked a question about this on the consent form that you will have to sign before
you are entered into the study.
6. What will happen to any samples I give?
This section is only relevant if you have agreed to give consent for any surplus
pathology samples and a blood sample to be kept for future kidney cancer research.
A separate information sheet will provide further information on this. Please ask
your doctor if this has not been given to you already.
7. Will any genetic tests be done?
This section is only relevant if you have agreed to give consent for any surplus
pathology samples and a blood sample to be kept for future kidney cancer research.
Each person’s genetic make up may influence the way they respond to any medical
treatment – how well it works and what side effects occur. We plan to test a range
of genes and proteins from your blood and from your cancer that may influence this.
We would also like to test for any things in your genetic make up that might have
given you an increased risk of getting the cancer in the first place. These studies will
involve extracting DNA or other material from the tumour and blood to see whether,
in the future, it may be possible to predict which patients will benefit from which
treatment. These tests will have no impact on the treatment you receive, and the
results of these tests will remain anonymised and will have no impact on you (or
your family).
MRC SORCE
SORCE Version 1.2
100
8. What will happen to the results of the research study?
During the course of the trial, which for each patient will last at least 8 years, an
expert committee will consider the progress of the research at regular intervals. This
is so that if one of the treatment plans turns out to be substantially inferior to the
others, this will be detected and stopped before the end of the trial. The information
from the trial will be released to Bayer. If the result shows a benefit, they may
choose to use this information to extend their license to sell sorafenib for patients
like you in the future.
The results of the study and the additional genetic research described above will be
presented after the completion of the trial at international scientific meetings and
published in a leading medical journal. At no point in the analysis or publication will
any information about the identity of participants be revealed. A copy of the results
will be available to you or your family on request. The regulatory authorities have
given their permission for this trial to be undertaken and we will report to them in
confidence any unexpected reactions that occur.
9. Who is organising and funding the research?
The study is being sponsored by the Medical Research Council (MRC), which
undertakes public sector research. The study is being organised by the MRC Clinical
Trials Unit, based in London and has been funded by them and by CTAAC and TRICC
(UK cancer research funding committees). The drug company Bayer is providing an
educational grant to support the running of the trial and is supplying sorafenib and
placebo free of charge. The (name of hospital) will receive a small payment from
Bayer to help provide some of the extra support needed to conduct the research
properly. No other funding is available.
10. Who has reviewed the study?
As well as a review by the funding bodies listed above, the study has been reviewed
and approved by the National Cancer Research Institute (NCRI) Kidney Cancer
Clinical Studies Group and approved for inclusion in the national portfolio of kidney
cancer trials. The study has also been given a favourable ethical opinion for conduct
in the NHS by the South East Research Ethics Committee.
MRC SORCE
SORCE Version 1.2
101
11. Further information
If you have any further questions about your illness or clinical trials, please discuss
them with your doctor. You may also find it helpful to contact CancerBACUP, an
independent patient advisory group (Freephone: 0808 800 1234;
http://www.cancerbacup.org.uk/Home) or visit the Cancer Research UK website
(http://www.cancerhelp.org.uk).
Once again, we would like to thank you for taking the time to read this information
and for considering taking part in this study.
Contact Details:
Contact names and telephone numbers (site-specific): <Please provide the patient with contact information including the name of their
treating physician and a 24 hour telephone contact number>
.....................................................................................................................................
You may also find it helpful to contact:
CancerBACUP, an independent patient advisory group (Freephone: 0808 800 1234;
http://www.cancerbacup.org.uk/Home)
Cancer Research UK website http://www.cancerhelp.org.uk
Consumers for Ethics in Research website http://www.ceres.org.uk/index.html
Thank you for taking the time to read this information and for considering taking part
in this study.
Appendix 12: TRANSORCE Patient Consent Form
Centre Name & Number: ………………………………….. Patient ID Number: ………………………………………….
Date and Version: February 2007 V1.1
TRANSORCE: Collection of Pathology and blood samples for use in kidney cancer research
Please initial boxes:
1. I have read and understand the patient information sheet for the above study
and have had the opportunity to ask questions and discuss it with my doctor.
2. I agree to samples from my cancer, removed during surgery, being used for research in the above project. I understand that I am free to withdraw my
approval for use of the samples at any time without giving a reason and
without affecting my medical care.
3. I agree to give sample(s) of blood for research in the above study. I understand how the sample(s) will be collected, that giving sample(s) is
voluntary and that I am free to withdraw my approval for use of the sample(s)
at any time without giving a reason and without my medical care or legal rights being affected.
4. I give permission for my name to be registered with the Office of National
Statistics (ONS) or traced via the NHS Strategic Tracing Service should I lose contact with my hospital doctor. I give permission for information about my
health status to be obtained from the ONS and/or the NHS Strategic Tracing
Service by the Medical Research Council if necessary.
5. I agree that the samples and information collected about me will be stored on behalf of the (MRC) for use in future projects. I understand that some of
these projects may be carried out by researchers other than the MRC, including researchers working for commercial (including pharmaceutical) companies.
6. I understand that future research using the samples I give may include
genetic research aimed at understanding the genetic influences on primary kidney cancer, but the results of these investigations are unlikely to have any
implications for me personally.
7. I understand that I shall not benefit financially if future research leads to the
development of new treatments or medical tests.
Name of Patient Date Signature
Name of Person taking consent Date Signature
(Principal Investigator or authorised delegate) (3 copies: 1 patient, 1 for the researcher and 1 to be kept with hospital notes)
Affix patient sticker here
[To be presented on local headed paper]
Appendix 13: Patient Consent Form (SORCE)
Centre Name & Number: ………………………………….. Patient ID Number: ………………………………………….
Date and Version: February 2007 V1.1
SORCE: A phase III study comparing sorafenib with placebo in patients who have kidney cancer removed
Please initial boxes:
1. I confirm that I have read and understand the SORCE Patient Information
sheet dated ……………………. (Version …………..) and I have the opportunity to ask questions and discuss it with my doctor.
2. I understand that my participation is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal
rights being affected.
3. I understand that sections of any of my medical notes may be looked at by
individuals from organisations involved in developing and running the trial (e.g. MRC CTU or Bayer) or from regulatory authorities where it is relevant to
my taking part in this research. I give permission for these individuals to have access to my records.
4. I give permission for my name to be registered with the Office of National
Statistics (ONS) or traced via the NHS Strategic Tracing Service should I lose contact with my hospital doctor. I give permission for information about my
health status to be obtained from the ONS and/or the NHS Strategic Tracing
Service by the Medical Research Council if necessary.
5. I agree to take part in the SORCE trial.
6. I give permission for my GP to be informed of my inclusion in this study.
I agree to take part in the above study
Name of Patient Date Signature
Name of Person taking consent Date Signature (Principal Investigator or authorised delegate)
(3 copies: 1 for patient, 1 for researcher and 1 to be kept with hospital notes)
Affix patient sticker here
[To be presented on local headed paper]
Appendix 14: SORCE GP Letter Centre Name & Number: …………………………………..
Patient ID Number: …………………………………………. Date and Version: May 2007 V1.2
SORCE: A phase III study comparing sorafenib with placebo in patients who have kidney cancer removed ISRCTN:
Dear Dr ____________
Your patient, ________________ (date of birth dd/mm/yyyy), has been diagnosed with Kidney Cancer. Following discussion of treatment options and review of the patient information sheets, (s)he has consented to enter the SORCE trial. SORCE is a double-blind placebo controlled study with patients being allocated to receive one of the following treatment plans:
3 years placebo or 1 year sorafenib & 2 years placebo or
3 years sorafenib
The expected side effects whilst taking sorafenib include hypertension, fatigue, diarrhoea, hand/foot reaction, rash, alopecia and flushing. If the patient develops
hypertension then this should be treated according to the local practise guidelines.
Patients on the trial will have their blood pressure monitored weekly during the first 6 weeks of treatment on the study. These measurements will co-incide with hospital visits at week 3 and 6. If the patient prefers we would like the measurements at
weeks 1, 2, 4 and 5 to be taken by you, their GP, or a practice nurse and recorded on the patient card which the patient is given when they are randomised into the trial. We hope that this will be possible in your practise.
Please find enclosed a copy of the patient information sheet and a summary of the trial. You will be kept up to date with your patient’s progress but if you have any
concerns or questions regarding this study please contact the responsible doctor: Dr ……………………………………….. at …………………………………………… (Hospital)
Tel: ………………………………. Kind regards,
Name Position
Affix patient sticker here
[To be presented on local headed paper]
MRC SORCE
SORCE Version 1.2
105
Appendix 15: SORCE Trial Summary for GPs
Trial Design and Rationale
SORCE is a multi-centre randomised phase III double-blind placebo-controlled study
examining the efficacy and tolerability of sorafenib (Nexavar) in patients with
resected (total or partial) primary renal cell carcinoma (RCC) at high or intermediate
risk or relapse. Patients will be randomised to one of three treatment arms in the
ratio 2:3:3.
Patients studied
Patients who have had an RCC resected are eligible for randomisation into SORCE
providing they are at intermediate or high risk of relapse and satisfy the
inclusion/exclusion criteria.
Treatment of Patients in the Trial
Patients will be randomly assigned to one of 3 arms: 3 years of placebo (Arm A), 1
year sorafenib followed by 2 years placebo (Arm B) or 3 years sorafenib (Arm C).
Sorafenib will be given at 400 mg po (per oral) bd doses. Patients with disease
progression who progress on Arms A or B within 3 years of start of treatment whilst
on placebo will be offered compassionate use of sorafenib at the standard dose of
400 mg po bd until further progression/toxicity.
Outcome Measures
The primary outcome measure is disease free survival (DFS) (i.e. time from
randomisation to first evidence of local recurrence or distant metastases or death
from RCC). The secondary outcome measures include RCC-specific survival time (i.e.
time to death from RCC), overall survival (OS), cost effectiveness, toxicity, biological
characteristics of resected primary RCC (VHL, VEGFR2, FGF2, B-RAF, MEK, ERK) and
corroboration of Leibovich Prognostic Score.
MRC SORCE
SORCE Version 1.2
106
Appendix 16: Case Report Forms
MRC SORCE
SORCE Version 1.2
107
MRC SORCE
SORCE Version 1.2
108
MRC SORCE
SORCE Version 1.2
109
MRC SORCE
SORCE Version 1.2
110
MRC SORCE
SORCE Version 1.2
111
MRC SORCE
SORCE Version 1.2
112
MRC SORCE
SORCE Version 1.2
113
MRC SORCE
SORCE Version 1.2
114
MRC SORCE
SORCE Version 1.2
115
MRC SORCE
SORCE Version 1.2
116
MRC SORCE
SORCE Version 1.2
117
MRC SORCE
SORCE Version 1.2
118
MRC SORCE
SORCE Version 1.2
119
MRC SORCE
SORCE Version 1.2
120
MRC SORCE
SORCE Version 1.2
121
MRC SORCE
SORCE Version 1.2
122
MRC SORCE
SORCE Version 1.2
123
MRC SORCE
SORCE Version 1.2
124
MRC SORCE
SORCE Version 1.2
125
MRC SORCE
SORCE Version 1.2
126
MRC SORCE
SORCE Version 1.2
127
MRC SORCE
SORCE Version 1.2
128
RE05 Assessment time points STAGE OF TREATMENT VISITS TIME POINT
WEEKS FORM No.
RADIOLOGY
TRANSORCE
Baseline
- - 1,2
SORCE Baseline
1 0 3,4,12
CT scan
Treatment 1 6*
2 6*
2 3 5,6,12
4 6*
5 6*
3 6 5,6,12
4 12 (3 MONTHS) 5,7,12 Chest x-ray
5 24 (6 MONTHS) 5,7,12 CT scan
6 9 months
5,7,12 Chest x-ray
12 months (1 year) 5,7,12 CT scan
15 months 5,7,12 Chest x-ray
18 months 5,7,12 CT scan
21 months 5,7,12 Chest x-ray
24 months (2 years) 5,7,12 CT scan
27 months 5,7,12 Chest x-ray
30 months 5,7,12 CT scan
33 months 5,7,12 Chest x-ray
36 months (3 years) 5,7,8,12 CT scan
Follow Up 6 monthly till 5 years 7,10,12 Chest-x-ray
ANNUALLY thereafter 7,10,12 Chest x-ray
Numbering for SORCE/RE05 CRFS
1. TRANSORCE Registration
2. PATHOLOGY tracking form 3. Randomisation/Pre treatment
4. Surgery 5. Treatment
6. Blood pressure monitoring form* (can be recorded by GP on patient card)
7. Disease Assessment form 8. End of treatment
9. First progression form (To be completed when first progression occurs) 10. Follow up
11. Death Form (To be completed upon patients death) 12. EQ-5D
13. SAE (to be completed as required)
14. Pregnancy monitoring form 15. Emergency Unblinding form