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STAMPEDE
Systemic Therapy in Advancing or
Metastatic Prostate cancer: Evaluation of
Drug Efficacy
Karen Sanders
STAMPEDE Trial Manager
Sponsor number:
ISRCTN number:
EUDRACT number:
CTA number:
MRC PR08
ISRCTN78818544
2004-000193-31
00316/0026/001-0001
June-2010
TRIAL DESIGN
June-2010
Design rationale
• STAMPEDE is 6-arm, 5-stage randomised
controlled trial
 3 investigational drugs
• Using Multi-Arm Multi-Stage methodology
 MAMS design
• MAMS design permits rapid comparison and
concurrent testing of treatments
June-2010
Trial Design
A
Hormone therapy (HT) alone
B
HT + zoledronic acid
C
HT + docetaxel
D
HT + celecoxib
E
HT + zoledronic acid + docetaxel
F
HT + zoledronic acid + celecoxib
Control
R
A
N
D
Eligible patient
with prostate
cancer
O
M
I
S
E
June-2010
Trial Design Stages
Stage
Pilot
Activity I-III
Efficacy IV
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
June-2010
PATIENT SELECTION CRITERIA
June-2010
Main Inclusion Criteria
• Newly diagnosed high risk patients with one of
 Any 2 out of the following 3
• Stage T3/4 N0 M0
• PSA  40ng/ml
• Gleason sum score 8-10
 Stage Tany N+ M0 or Tany Nany M+
 Multiple sclerotic bone metastases with a PSA  100ng/ml
• Previously treated relapsing patients with either
 PSA  4ng/ml and rising with doubling time less than 6
months
 PSA  20ng/ml
 N+
 M+
June-2010
Inclusion/Exclusion Criteria
• 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
June-2010
Hormone Therapy Before
Randomisation
• It is preferable that patients are not started
on hormones prior to randomisation
 No more than 12 weeks before
 PSA measurement taken before HT treatment
June-2010
Screening Procedures
• Patients identified




CT or MRI of pelvis and abdomen
Bone Scan
Chest X-ray and ECG
PSA Test
• Within 8 Weeks of Randomisation
 Blood Tests
June-2010
TREATMENT ADMINISTRATION
June-2010
Hormone Therapy
Three acceptable approaches:
• Bilateral orchidectomy
 Total or subcapsular
• LHRH analogues
 Used according to local practice
 Prophylactic anti-androgens recommended
• Anti-Androgens
 M0 patients only
 Monotherapy according to local practice
June-2010
Zoledronic acid
• Zoledronic acid 4mg 15min IV infusion
 Every 3 weeks for 6 treatments
 Then every 4 weeks
• Patients should also receive
 500mg calcium oral supplement
 400IU vitamin D oral supplement
 Available as a combination tablet
• Continues until the soonest of:
 Maximum of 2 years
 disease (including PSA) progression
June-2010
Docetaxel
• Docetaxel 75mg/m2
 Day 1 as 1hr IV infusion
 Max 160mg
• Patients should also receive
 Prednisolone 5mg bid daily for 21 days
• Continues:
 Cycle repeated every 3 weeks for 6 cycles
June-2010
Celecoxib
• Celecoxib 400mg
 bid
• Continues until the soonest of:
 Maximum of 1 year
 Disease (including PSA) progression
June-2010
Radiotherapy
• Radiotherapy permitted for suitable patients
• 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
 and after any docetaxel toxicity settled
June-2010
ASSESSMENTS & FOLLOW-UP
June-2010
Follow-up schedule
6 weekly 0 to 24 weeks
12 weekly up to 2 years
6 monthly up to 5 years
Annually thereafter
June-2010
Assessment of Treatment
Failure
• New lesions
 CT scan
• Increase in baseline lesions
 CT scan
• Biochemical
 Rate of fall of PSA and the level of the PSA nadir
 PSA nadir will be sent to responsible clinician confirming
the PSA level which would be taken as progression.
• Death from prostate cancer
June-2010
Defining PSA Nadir & PSA
Failure
• 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
June-2010
PSA Failure Categories
Groups for defining late PSA failure
Based on nadir PSA before 24 weeks on trial
80
Group A
60
40
Group B
20
0
Group C
0
20
40
60
80
100
120
Pre-hormone PSA (ng/ml)
--A: PSA nadir > 50% pre-hormone PSA ---> PSA failure now
B: PSA nadir < 50% pre-hormone PSA but >4ng/ml ---> refer to PSA failure graph
C: PSA nadir < 50% pre-hormone PSA and <4ng/ml ---> refer to PSA failure graph
June-2010
Defining PSA Relapse
• For patients in group A – Failed at time zero
• For Patients in group B – Relapse occurs
when PSA increases by 50% above nadir
• For Patients in group C – Relapse occurs
when PSA increases by 50% above nadir or
goes above 4ng/ml, whichever is greatest
June-2010
DRUG SUPPLY
June-2010
Drug Supply & Support
• Novartis
 Supplying free Zoledronic Acid
 Providing an educational grant to support some
central work
• Pfizer
 Supplying free Celecoxib
 Providing funds to distribute drug to centres
• Sanofi-Aventis
 Providing an educational grant
 Supplying Docetaxel at a discounted price of buy
1 get 2 free
June-2010
Drug Supply & Support
• Department of Health
 Central subvention provided
 £1,787 per patient randomised to arms C and E
of the trial and prescribed docetaxel.
 Payable in respect of a hospital trust
randomising more than 3 patients
June-2010
Drug Ordering and Labelled
• Celecoxib and Zoledronic Acid
 Ordered by MRC CTU at accreditation and on
subsequent request from centres
• Docetaxel
 Ordered by centre pharmacist
• All drugs
 To be labelled by the pharmacist using labels
provided
June-2010
CURRENT ACCRUAL
June-2010
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


1643 patients have been randomised
17-June-2010
June-2010
Accrual
Cumulative randomisation overall
2100
1800
1500
1200
pilot phase
complete
900
600
300
Oct-11
Jul-11
Jan-11
Jul-10
Jan-10
Jul-09
Jan-09
Jul-08
Jan-08
Jul-07
Jan-07
Jul-06
Jan-06
Oct-05
0
Date of randomisation
Observed
Expected
There are many hundreds of successful accrual scenarios for recruitment to
ST AMPEDE in the Statistical Design Document. One is shown here.
June-2010
Patient Characteristics
Age (years) at randomisation median (quartiles)
65 (60-70)
PSA (ng/ml) at randomisation median (quartiles)
66 (24-177)
WHO performance status (0 Vs 1 Vs 2+)
1210 vs 338 vs
16
Bone mets at randomisation n (%)
789 (50%)
RT planned n (%)
379 (24%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
High risk newly diagnosed pts n (%)
Previously treated/relapsing pts n (%)
1535 vs 22 vs 8
1460 (93%)
105 (7%)
Data from 30-Apr-2010
June-2010
TRIAL COMMITTEES
AND CONTACTS
June-2010
Trial Management Group
Nick James
Noel Clarke
Malcolm Mason
Oncologist; CI, Chair,
Urologist; Vice-Chair
Oncologist; Vice-Chair
Birmingham, UK
Manchester, UK
Cardiff, UK
John Anderson
David Dearnaley
John Dwyer
John Masters
Rick Popert
Marc Schulper
Andrew Stanley
George Thalmann
Urologist
Oncologist
Patient representative
Pathologist
Oncologist
Health Economist
Pharmacist
Oncologist
Sheffield, UK
Sutton, UK
Stockport, UK
London, UK
London, UK
York, UK
Birmingham, UK
Bern, CH
Elizabeth Clark
Pierre Fustier
Charlene Griffith
Gordana Jovic
Max Parmar
Karen Sanders
Matthew Sydes
Data Manager
Trial Coordinator
Data Manager
Statistician
Statistician
Trial Manager
CTU Lead/Trial Statistician
MRC CTU,
SAKK, CH
MRC CTU,
MRC CTU,
MRC CTU,
MRC CTU,
MRC CTU,
UK
UK
UK
UK
UK
UK
June-2010
Contact us
Karen Sanders
Trial Manager
MRC Clinical Trials Unit
T: 0207 670 4831
E: [email protected]
Charlene Griffith & Liz Clark
Data Managers
MRC Clinical Trials Unit
T: 0207 670 4882/4794
E: [email protected]
June-2010