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]