STAMPEDE
Systemic Therapy in Advancing or
Metastatic Prostate cancer: Evaluation of
Drug Efficacy
How to report Progressions and RT data
Sponsor number:
ISRCTN number:
EUDRACT number:
CTA number:
MRC Clinical Trials Unit
MRC PR08
ISRCTN78818544
2004-000193-31
00316/0026/001-0001
Design rationale

STAMPEDE uses multi-arm multi-stage methodology

MAMS design permits rapid comparison and concurrent testing of
treatments

Currently using 1 investigational drug + research radiotherapy

Issues in applying multi-arm multi-stage (MAMS)- methodology to a
clinical trial in prostate cancer:the MRC STAMPEDE trial. M.Sydes et
al., Trials.10. 39.
http://www.trialsjournal.com/content/10/1/39 (Open access)
MRC Clinical Trials Unit
Timelines: initial plans
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT-alone
B
ADT + zoledronic acid
C
ADT + docetaxel
D
ADT + celecoxib
E
ADT + zoledronic acid + docetaxel
F
ADT + zoledronic acid + celecoxib
Past accrual
Possible future accrual
MRC Clinical Trials Unit
Follow-up
Accrual: end of Activity Stage II
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT-alone
B
ADT + zoledronic acid
C
ADT + docetaxel
D
E
F
ADT + celecoxib
ADT + zoledronic acid + docetaxel
ADT + zoledronic acid + celecoxib
Past accrual
Possible future accrual
MRC Clinical Trials Unit
Follow-up
Timelines: from Nov-2011
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT-alone
B
ADT + zoledronic acid
C
ADT + docetaxel
D
E
F
ADT + celecoxib
ADT + zoledronic acid + docetaxel
ADT + zoledronic acid + celecoxib
G
ADT + abiraterone
Past accrual
Possible future accrual
MRC Clinical Trials Unit
Follow-up
Timelines: from Jan-2013
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT-alone
B
ADT + zoledronic acid
C
ADT + docetaxel
D
ADT + celecoxib
E
F
ADT + zoledronic acid + docetaxel
ADT + zoledronic acid + celecoxib
G
ADT + abiraterone
H M1 only
ADT + RT
Past accrual
Possible future accrual
MRC Clinical Trials Unit
Follow-up
Timelines: from March-2013
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT-alone
B
ADT + zoledronic acid
C
ADT + docetaxel
D
ADT + celecoxib
E
F
ADT + zoledronic acid + docetaxel
ADT + zoledronic acid + celecoxib
G
ADT + abiraterone
H M1 only
ADT + RT
Past accrual
Possible future accrual
MRC Clinical Trials Unit
Follow-up
Arms recruiting protocol 9.0
MRC Clinical Trials Unit
Current comparison Design: Protocol v10
MRC Clinical Trials Unit
Main Inclusion Criteria
Four broad disease categories:
• Newly diagnosed high risk T3/4 N0 M0
• Newly diagnosed node positive Tany N+ M0
• Newly diagnosed metastatic Tany Nany M+
• Previously treated now relapsing:
•
•
•
•
PSA  4ng/ml and rising with doubling time < 6 months
PSA  20ng/ml
N+
M+
Please see protocol section 4.1 and 4.2 for complete details about inclusion
and exclusion criteria
MRC Clinical Trials Unit
How to report progression events
MRC Clinical Trials Unit
STAMPEDE Follow-up schedule
6 weekly
0 to 24 weeks
12 weekly
up to 2 years
6 monthly
up to 5 years
Annually
thereafter
• Follow-up dates will be sent to you on a treatment and follow-up
schedule each time you randomise a patient.
• Please complete a follow-up form for each visit
MRC Clinical Trials Unit
Assessment of Treatment Failure
Types of progression:
1.
2.
3.
4.
5.
Biochemical
Local
Lymph node
Distant metastatic
Skeletal related event
Each type of progression only needs to be reported once.
Please complete an ‘additional treatment update form’ if a patient
receives additional treatment for a progression that you have already
reported.
MRC Clinical Trials Unit
Defining PSA Nadir & PSA Failure Categories
• PSA Nadir
• Lowest reported PSA level
• Between randomisation and 24 weeks
• PSA Failure
• Depends on baseline PSA measurement and PSA nadir
• 3 possible PSA failure categories, A, B and C
MRC Clinical Trials Unit
Defining PSA Relapse
3 PSA failure categories:
• PSA Failure Category A – When nadir is > 50% baseline
(failed at time zero)
• PSA Failure Category B – Nadir is over 4ng/ml. Relapse
occurs when PSA increases by 50% above nadir
• PSA Failure Category C – Nadir is under 4ng/ml. Relapse
occurs when PSA increases by 50% above nadir or above
4ng/ml, whichever is greatest
MRC Clinical Trials Unit
Defining PSA Relapse
• Ensure a confirmatory PSA test is done between 1 week and 3
months:
• if value is ≥ PSA progression value then report biochemical
progression
• If the clinician decides that a patient has biochemically progressed
before progression value is met (e.g. by adding anti-androgens):
• Report progression as normal
MRC Clinical Trials Unit
Progression letters
• PSA progression letters are sent out every 3 months for patients
whom we have received their 24 week follow-up form
Alternatively:
•
Please check appendix J for details of how to calculate the
progression value
OR
• Contact the trial team for help
MRC Clinical Trials Unit
PSA Progression categories: examples
Progression
category
Pre-HT
PSA
(ng/ml)
PSA Nadir
(ng/ml)
PSA progression
Value
(ng/ml)
A
19
100
400 (at week 24)
B
518
171.6
257.4
C
489.2
1.9
4.0
MRC Clinical Trials Unit
Assessment of Treatment Duration– Arm G
For M+ patients, treatment should continue until all progressions
occur:
• PSA progression
• Radiological progression (appearance of new lesions or
progression of existing lesions)
• Clinical progression (defined as new cancer-related symptoms)
It is accepted that these flexible criteria for stopping treatment with
abiraterone are open to the investigator’s interpretation and
discretion.
• All progressions must be reported as per the other arms
MRC Clinical Trials Unit
Assessment of Treatment Duration– Arm G
For N0M0 patients or N+M0 patients planned for RT treatment
should continue until:
• 2 years or
• Disease progression as defined for M+ patients, whichever is
sooner
For patients with N+M0 disease not planned for radical
radiotherapy should continue until:
•
Disease progression as defined for M+ patients
MRC Clinical Trials Unit
Reporting progressions on CRFs
In case of progression, complete and return:
• Follow up form for the relevant visit (e.g. week 6, 12, 18,
24 etc)
• Progression and Additional Treatment form
• End of treatment form (if applicable)
• Death form (if applicable)
MRC Clinical Trials Unit
Reporting progressions on CRFs
For patients on Arms A, B, C and E:
•
Please continue to follow up as normal and report data on Follow
up (post-progression) form
•
Please ensure that any second-line treatments are reported on
the form
For patients on Arm G:
•
•
Please continue to follow up as normal but report data on Follow
up form until all types of progression occur
Please ensure no further second-line treatment is given until:
• all types of progressions are reported
• trial abiraterone treatment is stopped
MRC Clinical Trials Unit
Some examples…
Follow up form
MRC Clinical Trials Unit
Some examples…
Progression and Additional Treatment Form
MRC Clinical Trials Unit
What to do post-progression
•
Continue to follow up patients as normal until death
•
Complete Follow up (Post-progression) form at each follow up
visit
•
Ensure additional treatment post progression are reported using
the Additional Treatments form
• In case of missed follow up, please return the Follow up form as
normal indicating
• “Missed visit“ at the top of the form
• PSA value (if known)
• Week number
MRC Clinical Trials Unit
How to report RT data
MRC Clinical Trials Unit
Radiotherapy in STAMPEDE
MRC Clinical Trials Unit
Standard-of-care radiotherapy
• N0M0 patients: Investigators should give radiotherapy (RT)
to patients with N0M0 disease, in accordance with the recent
data from the PR07 and SPCG trials
• If there is an intention to omit radiotherapy in patients with
N0M0 disease this must be discussed with the MRC CTU
before consent
• N+M0 patients: the benefit of radiotherapy in this group is
at present uncertain. Investigators will be asked to state their
intention with regard to planned radiotherapy in this group at
randomisation
• RT given 6 to 9 months after randomisation
MRC Clinical Trials Unit
Standard-of-care radiotherapy
MRC Clinical Trials Unit
Research (M1) Prostate Radiotherapy
• The use of radiotherapy to the prostate will retard
progression of the metastases in men presenting with
metastatic prostate cancer
• The primary tumour may be required to stimulate
disseminated tumour cells to grow into metastases
• Supporting evidence in renal and prostate cancer
(SWOG 8949, EORTC 30947, MRC PR07 /NCIC PR.3
trials)
MRC Clinical Trials Unit
Research (M1) Prostate Radiotherapy
MRC Clinical Trials Unit
Reporting radiotherapy data
For patients who receive a primary or research course of
radiotherapy, complete and return
• Radiotherapy detail form
• Radiotherapy acute toxicity form
For patients who receive a palliative course of radiotherapy,
complete and return
•
Palliative radiotherapy form
MRC Clinical Trials Unit
Reporting radiotherapy data
• For patients who receive RT, RT detail form should be
completed when the patient's course is completed
• For standard-of-care RT, please ensure forms are completed
and returned after a maximum of 12 months postrandomisation
• For research (M1) RT to prostate please ensure forms are
completed and returned after a maximum of 8 weeks postrandomisation
• For patients who do not receive primary RT, it should be
completed 10 months after randomisation to confirm that
RT was not given
MRC Clinical Trials Unit
Some examples…
RT detail form
MRC Clinical Trials Unit
Some examples…
RT acute toxicity form
MRC Clinical Trials Unit
Conclusion
•
Ensure Failure Free Survival events (e.g biochemical
progression) is reported appropriately
• Arm-specific rules
•
•
Treatment duration
Follow up continues until death (overall survival)
• Report RT information:
• Standard-of-care RT (M0N0 or M0N+)
• Research RT to prostate (newly diagnosed M+)
MRC Clinical Trials Unit
TRIAL COMMITTEES
AND CONTACTS
MRC Clinical Trials Unit
Trial Management Group
Nick James
Noel Clarke
Malcolm Mason
Oncologist; CI, Chair,
Urologist; Vice-Chair
Oncologist; Vice-Chair
Birmingham, UK
Manchester, UK
Cardiff, UK
Alastair Ritchie
David Dearnaley
Chris Parker
Robert Millman
John Masters
Martin Russell
Marc Schulper
Andrew Stanley
George Thalmann
Daniel Aebersold
Estelle Cassoly
Trial Surgeon
Oncologist
Oncologist
Patient representative
Pathologist
Oncologist
Health Economist
Pharmacist
Oncologist
Clinical Oncologist
Trial Coordinator
MRC CTU
Sutton, UK
Sutton, UK
Stockport, UK
London, UK
Glasgow, UK
York, UK
Birmingham, UK
Bern, CH
Bern, CH
SAKK, CH
Claire Amos
Francesca Schiavone
Alanna Brown
Dominic Hague
Katie Ward
Peter Vaughan
Melissa Spears
Max Parmar
Matthew Sydes
Clinical Project Manager
Clinical Trial Manager
Clinical Trial Manager
Data Manager
Data Manager
Data Manager
Trial Statistician
CTU Director
CTU Lead/Senior Trial Statistician
MRC
MRC
MRC
MRC
MRC
MRC
MRC
MRC
MRC
MRC Clinical Trials Unit
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
UK
UK
UK
UK
UK
UK
UK
UK
UK
Contact us
Web: www.stampedetrial.org
MRC
Francesca Schiavone
Clinical Trial Manager
T: +44 (0) 207 670 4632
E: mrcctu.stampede@ucl.ac.uk
Alanna Brown
Clinical Trial Manager
T: +44 (0) 207 670 4882
E: mrcctu.stampede@ucl.ac.uk
Dominic Hague, Katie Ward, Peter Vaughan
STAMPEDE Data Managers
T: +44 (0) 207 670 4809 / 4794 / 4947
E: mrcctu.stampede@ucl.ac.uk
MRC Clinical Trials Unit