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PSA Failure Category A
STAMPEDE
Systemic Therapy in Advancing or
Metastatic Prostate cancer: Evaluation of
Drug Efficacy
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
Trial Design Stages
Stage
Pilot
Activity I-III
Efficacy IV
MRC Clinical Trials Unit
Outcome Measures
Primary
Secondary
Safety
Feasibility
Failure-free survival
Overall survival
Toxicity
Skeletal-related events
Overall survival
Failure-free survival
Toxicity
Skeletal-related events
Quality of life
Current comparison Design: Protocol v10
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
PATIENT SELECTION CRITERIA
MRC Clinical Trials Unit
Main Inclusion Criteria
Newly diagnosed high risk patients T3/4 N0 M0 with:
•
At least two of:PSA≥40ng/ml or Gleason sum score 8-10
•
And intention to treat with radical radiotherapy (unless there is a
contra-indication; exemption must be sought in advance of consent, after
discussion with MRC CTU)
Newly diagnosed metastatic or nodal disease
•
Stage Tany N+ M0 or Tany Nany M+
Previously treated relapsing patients with either
•
PSA  4ng/ml and rising with doubling time < 6 months
•
PSA  20ng/ml
•
N+
•
M+
MRC Clinical Trials Unit
Inclusion/Exclusion Criteria

Histological confirmation of prostate cancer

Intention to treat with long term HT

WHO PS 0,1 or 2

Adequate cardiovascular history

No major dental extractions planned within next 2 years
Please see protocol section 4.1 and 4.2 for complete details about
inclusion and exclusion
MRC Clinical Trials Unit
Selection criteria for M1/RT comparison
• Newly diagnosed prostate cancer
• Demonstrable M1 disease
• No contraindication to radiotherapy
• No previous radical prostatectomy
• Meets all other eligibility criteria
Protocol section 4.3 for more information
MRC Clinical Trials Unit
Cardiovascular exclusion criteria
•
Patients with significant cardiovascular disease such as:
• MI less than 6 months prior to randomisation
• Arterial thrombotic events less than 6 months prior to
randomisation
• Clinically significant cardiac failure requiring treatment (NYHA IIIV)
• Cerebrovascular disease less than 2 years prior to randomisation
• Close cardiovascular monitoring recommended for patients in
arm G
MRC Clinical Trials Unit
Hormone Therapy Before Randomisation
It is preferable that patients are not started on hormones prior to
randomisation but if they are then:
• No more than 12 weeks of LHRH before randomisation
• Orchidectomy should be performed no more than 12 weeks
before randomisation
• Patients with bilateral orchidectomy should start treatment within
4 weeks from surgery
• No more than 14 weeks of anti-androgens before
randomisation
• PSA measurement MUST be taken before HT treatment starts!
MRC Clinical Trials Unit
Clarification of HT prior randomisation
See Appendix L
MRC Clinical Trials Unit
Screening Procedures
Patients identified
• CT or MRI of pelvis and abdomen
• Bone Scan (or equivalent imagining)
• Chest X-ray (unless chest included in CT)
• ECG
• PSA Test
Within 8 Weeks of Randomisation
• Blood Tests
• (See protocol section 4.3)
MRC Clinical Trials Unit
TREATMENT ADMINISTRATION
MRC Clinical Trials Unit
Hormone Therapy
Three acceptable approaches:
• Bilateral orchidectomy
• Total or sub-capsular
• LHRH agonist or antagonist
• Used according to local practice
• Prophylactic anti-androgens recommended
Anti-androgen monotherapy is not allowed
MRC Clinical Trials Unit
Abiraterone Treatment
• Recommended dose is 4 x 250mg tablets as a single daily
dose.
• Taken with low dose prednisone or prednisolone.
Recommended dose of steroid is 5mg
• Taking the tablets with food increases systemic exposure to
abiraterone. Abiraterone must not be taken with food. It
should be taken at least two hours after eating and no food
should be eaten for at least one hour after taking
abiraterone. Tablets should be swallowed whole with water.
MRC Clinical Trials Unit
Abiraterone - Monitoring
Patients on arm G require additional monitoring.
• Patients will require 2 weekly U+Es, LFTs and blood pressure
measurement for the first 12 weeks
• In the event of a missed dose of either abiraterone, prednisone or
prednisolone, treatment should be resumed the following day with
the usual daily dose.
• Please refer to protocol appendix G
MRC Clinical Trials Unit
Abiraterone: Hepatotoxicity
• If ALT > 5x ULN (Grade 3 toxicity) treatment should be
withheld.
• Following LFT return to baseline or Grade 1 reintroduce at
reduced dose (750mg daily). Serum transaminases should
be monitored every two weeks for three months & monthly
thereafter
• If hepatotoxicity recurs after the first dose reduction,
treatment discontinued.
• For severe hepatotoxicity (ALT ≥20x ULN), treatment
should be discontinued & not be reintroduced.
• Please refer to appendix G2 of the updated STAMPEDE
protocol
MRC Clinical Trials Unit
Contra-indication to abiraterone
•
•
Abiraterone inhibits enzymes CYP1A2 and CYP2D6
Interactions with:
• Betablockers/cardiac drugs
• Antidepressants
• Analgesics
• Anti-fungal agents
• Macrolide antibiotics
• Antiviral drugs for HIV infection
• Antitubercolosis drugs
• Anticonvulsants
See Appendix section G.4.3 for more details
MRC Clinical Trials Unit
Radiotherapy
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
• Recommended type, timing and dose in protocol section 6
• Intention to use RT stated at randomisation
• ensure no bias towards particular combinations of
systemic therapy with radiotherapy
• RT given 6 to 9 months after randomisation
MRC Clinical Trials Unit
Standard-of-care radiotherapy
MRC Clinical Trials Unit
Research radiotherapy: Hypothesis
•The use of radiotherapy to the prostate will retard
progression of the metastases in men presenting with
metastatic prostate cancer
MRC Clinical Trials Unit
Supporting evidence: metastatic renal carcinoma
SWOG 8949
EORTC 30947
Flanigan RC et al. NEJM 345(23):1655-9.
Mickisch GHJ et al. Lancet 358:966-70.
MRC Clinical Trials Unit
Supporting evidence: prostate cancer
Pre-prostatectomy
Post-prostatectomy
Weckermann JCO 2009; 27(10): 1549-56
Inference: The primary tumour may be required to
stimulate disseminated tumour cells to grow into metastases
MRC Clinical Trials Unit
Supporting evidence: SPCG-7
Early separation of OS curves
Widmark et al The Lancet 2009 373, 301-308
Other relevant trial: UK & Canada: MRC PR07 /NCIC PR.3
MRC Clinical Trials Unit
Research (M1) Prostate Radiotherapy
•RT schedule chosen by doctor and patient if
allocated
•RT to start within 4 weeks after randomisation
•Conformal RT or Intensity Modulated RT
MRC Clinical Trials Unit
Research (M1) Prostate Radiotherapy
Selection criteria:
• Newly diagnosed prostate cancer
• Demonstrable M1 disease (excluding local nodes)
• No contraindication to RT (e.g. no previous pelvic
RT)
• No previous radical prostatectomy
MRC Clinical Trials Unit
Research (M1) Prostate Radiotherapy
MRC Clinical Trials Unit
Radiotherapy
For patients who receive a primary or research course of
radiotherapy
• Radiotherapy detail form
• Radiotherapy acute toxicity form
MRC Clinical Trials Unit
Cost of radiotherapy
• No capacity issues raised following survey circulated
in Q1 2012
• M1/RT schedules as excess treatment cost
• 1 patient recruited month = 2 patients/year arm H
• Should be minimal impact
• NCRN adopted trial
MRC Clinical Trials Unit
Radiotherapy Quality Assurance
• No additional RTQA in sites that has participated in
clinical trials of prostate cancer irradiation
• RT01, CHHIP, PIVOTAL, RADICALS
• For sites which have not participated in such trials,
central review of plans for two non-trial patients
• All current STAMPEDE centres in UK delivering RT
already have RTQA
MRC Clinical Trials Unit
ASSESSMENTS & FOLLOW-UP
MRC Clinical Trials Unit
Identification and consent
• General PIS for all patients
• Identify which pt could not be allocated to arm H
• Verbally inform pts whether could or could not be
allocated to arm H
• Record correctly pt disease category on CRF
• Arm G patients to be re-consented at first available
follow up (patients on treatment only)
• Send copy of signed consent form to MRC CTU
MRC Clinical Trials Unit
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
Assessment of Treatment Failure – Arm G
For M+ patients, treatment should continue until clinical disease
progression
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.
• Patients might continue treatment beyond the first progression
event.
• All progressions must be reported as per the other arms.
MRC Clinical Trials Unit
Assessment of Treatment Failure – Arm G
For N0M0 patients or N+M0 patient undergoing radical radiotherapy
• Treatment duration = 2 years or disease progression as defined
for M+ patients, whichever is the sooner.
For patients with N+M0 disease not planned for radical radiotherapy,
• Treatment duration = to continue as for patients with M1 disease
until disease progression
Please call the trial team if you are unsure about whether a
patient should stop taking abiraterone.
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 – Failed at time zero
• PSA Failure Category B – Relapse occurs when PSA increases
by 50% above nadir
• PSA Failure Category C – Relapse occurs when PSA increases
by 50% above nadir or goes above 4ng/ml, whichever is greatest
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 K for details of how to calculate
the progression value.
MRC Clinical Trials Unit
DRUG SUPPLY
MRC Clinical Trials Unit
Drug Supply & Support
• Janssen
• Supplying free Abiraterone
• Abiraterone
• Ordered by centre pharmacist directly from B&C
• Pre-labelled with generic and trial-specific labels
MRC Clinical Trials Unit
Safety Reporting
•
•
•
•
ICH GCP Safety Reporting definitions apply to STAMPEDE
Protocol section 11: Events Terms and Definitions
Definition of an event depends on four factors:
Seriousness
• was the event serious?
Any adverse event or reaction that:
•Results in death
•Is life-threatening
•Requires hospitalisation or prolongation of existing hospitalisation
•Consist of a congenital anomaly or birth defect
•Other important medical condition
•
Causality
•
Expectedness
• was it related to the trial treatment?
• were the symptoms recognised side-effects of the treatment?
• NOT ‘we didn’t expect that to happen!’
• use List of Expected Toxicities
MRC Clinical Trials Unit
STAMPEDE: Clarifications and Exceptions
• The term “life threatening” refers to an event in which the patient
was at risk of death at the time of the event
• Hospitalisation is defined as an inpatient admission;
hospitalisation of pre-existing conditions do not constitute an SAE
• Pregnancy occurring in a STAMPEDE patient’s partner must be
reported to the MRC CTU within the same timelines as an SAE and
classified as “other important medical condition”
MRC Clinical Trials Unit
Notifications and responsibilities
• Investigators must notify the MRC CTU of all SAEs
from the time of randomisation until 30 days after
the last protocol treatment
• SAEs in Arm A patients must be reported until 2 years
and 2 months or progression
• SARs and SUSARs must be notified indefinitely
• Causality, expectedness and seriousness should
be assessed by a clinician responsible for the care of
the patient
• SAEs must be notified using the appropriate SAE form
by fax (fax number 02076704818)
MRC Clinical Trials Unit
Trial specific exemptions
• Disease progression
• Death as result of disease progression
• Elective hospitalisation and surgery for treatment of locally
advanced or metastatic cancer or its complications
• Elective hospitalisation for pre-existing conditions that have not
been exacerbated by trial treatment
• Elective hospitalisation for pre-existing conditions to simplify
treatment or procedures
MRC Clinical Trials Unit
Associated undesirable effects for RT
See Appendix G for more details on both
abiraterone and RT
MRC Clinical Trials Unit
STAMPEDE Accrual: July 2013
Total recruitment (July 2013): 4500 patients
MRC Clinical Trials Unit
Current Recruitment Status
First patient
•
17th October 2005
Accrual targets
•
Pilot Phase target was 210 patients
•
Pilot Phase target achieved in
March 2007
•
Overall target approximately 3300
patients
– (440 OS events on control
arm)
Observed accrual
•
4500 patients
•
Record month: July 2013 (159
patients recruited)
•
123 participating centres; 8 Swiss
centres
MRC Clinical Trials Unit
Patient Characteristics
Age (years) at randomisation median (quartiles)
65 (37-94)
PSA (ng/ml) at randomisation median (quartiles)
65 (23-188)
WHO performance status (0 Vs 1 Vs 2+)
3193 vs 858 vs
46
Bone mets at randomisation n (%)
2150 (52%)
RT planned n (%)
1189 (29%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
Data from April 2013
MRC Clinical Trials Unit
4019 vs 54 vs
19
Patient characteristics
Newly diagnosed M1
61%
Newly diagnosed N+M0
21%
Newly diagnosed N0M0
14%
Previously treated
3%
Bone mets at randomisation
2,150 (52%)
Liver mets at randomisation
61 (1.5%)
Lung mets at randomisation
104 (3%)
Distant node mets at randomisation
761 (19%)
Other mets at randomisation
173 (4%)
MRC Clinical Trials Unit
New comparison arm
• TMG considering further new research arm
• Survey sent to sites in early Feb for one possible
new comparison: Enzalutamide + Abiraterone
MRC Clinical Trials Unit
Case Report Forms
MRC Clinical Trials Unit
Case Report Forms
Please visit the STAMPEDE trial website to download the CRFs http://www.stampedetrial.org/centres/information_for_centres/crfs_and_com
pletion_guidelines.aspx
MRC Clinical Trials Unit
Prior to randomisation
These 4 forms should be filled out prior to randomisation:
1.
2.
3.
4.
Bone density risk factor questionnaire
Randomisation form
Baseline form
Cardiovascular form
MRC Clinical Trials Unit
Randomisation CRF
MRC Clinical Trials Unit
Randomisation CRF
MRC Clinical Trials Unit
Randomisation pack
Each time you randomise a patient we will send you a pack which
contains:
• Randomisation confirmation
• Treatment schedule
• FTA elute card kit & pathology form for the next patient
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: [email protected]
Alanna Brown
Clinical Trial Manager
T: +44 (0) 207 670 4882
E: [email protected]
Dominic Hague, Katie Ward
STAMPEDE Data Managers
T: +44 (0) 207 670 4809 / 4794 / 4947
E: [email protected]
MRC Clinical Trials Unit
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