Transcript Main title
STAMPEDE
Systemic Therapy in Advancing or
Metastatic Prostate cancer: Evaluation of
Drug Efficacy
Tom Fairfield
STAMPEDE Trial Manager
Sponsor number:
ISRCTN number:
EUDRACT number:
CTA number:
MRC PR08
ISRCTN78818544
2004-000193-31
00316/0026/001-0001
TRIAL DESIGN
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
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
R
A
N
D
Eligible patient
with prostate
cancer
O
M
I
S
E
Control
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
PATIENT SELECTION CRITERIA
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+
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
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
Screening Procedures
• Patients identifed
CT or MRI of pelvis and abdomen
Bone Scan
Chest X-ray and ECG
PSA Test
• Within 8 Weeks of Randomisation
Blood Tests
TREATMENT ADMINISTRATION
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
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
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
Celecoxib
• Celecoxib 400mg
bid
• Continues until the soonest of:
Maximum of 1 year
Disease (including PSA) progression
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
ASSESSMENTS & FOLLOW-UP
Follow-up schedule
6 weekly 0 to 24 weeks
12 weekly up to 2 years
6 monthly up to 5 years
Annually thereafter
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
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
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
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
120
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
DRUG SUPPLY
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
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
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
CURRENT ACCRUAL
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
2114 patients have been randomised
28th February 2011
Accrual
Patient Characteristics
Age (years) at randomisation median (quartiles)
65 (60-70)
PSA (ng/ml) at randomisation median (quartiles)
66 (23-183)
WHO performance status (0 Vs 1 Vs 2+)
Bone mets at randomisation n (%)
RT planned n (%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
High risk newly diagnosed pts n (%)
Previously treated/relapsing pts n (%)
Data from 28th Feb 2011
1628 vs 460 vs
25
1080 (51%)
521 (25%)
2069 vs 35 vs
10
1975 (93%)
139 (7%)
TRIAL COMMITTEES
AND CONTACTS
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
Martin Russell
Marc Schulper
Andrew Stanley
George Thalmann
Urologist
Oncologist
Patient representative
Pathologist
Oncologist
Health Economist
Pharmacist
Oncologist
Sheffield, UK
Sutton, UK
Stockport, UK
London, UK
Glasgow, UK
York, UK
Birmingham, UK
Bern, CH
Charlene Green
Gordana Jovic
Erika Kuettel
Max Parmar
Tom Fairfield
Matthew Sydes
Data Manager
Statistician
Trial Coordinator
Statistician
Trial Manager
CTU Lead/Trial Statistician
MRC CTU,
MRC CTU,
SAKK, CH
MRC CTU,
MRC CTU,
MRC CTU,
UK
UK
UK
UK
UK
Contact us
Tom Fairfield
Trial Manager
MRC Clinical Trials Unit
T: 0207 670 4831
E: [email protected]
Charlene Green
Data Manager
MRC Clinical Trials Unit
T: 0207 670 4882
E: [email protected]