STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy

1
STAMPEDESystemic Therapy in Advancing or
Metastatic Prostate cancer Evaluation of Drug
Efficacy

• Karen Sanders
• STAMPEDE Trial Manager

Sponsor number MRC PR08ISRCTN number
ISRCTN78818544EUDRACT number
2004-000193-31CTA number
00316/0026/001-0001
2
TRIAL DESIGN
3
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

4
Trial Design
5
Trial Design Stages

• Stage Outcome Measures
• Primary Secondary
• Pilot Safety Feasibility
• Activity I-III Failure-free survival Overall
  survival
• Toxicity
• Skeletal-related events
• Efficacy IV Overall survival Failure-free
  survival
• Toxicity
• Skeletal-related events
• Quality of life

6
PATIENT SELECTION CRITERIA
7
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

8
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

9
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

10
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

11
TREATMENT ADMINISTRATION
12
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

13
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

14
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

15
Celecoxib

• Celecoxib 400mg
• bid
• Continues until the soonest of
• Maximum of 1 year
• Disease (including PSA) progression

16
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

17
ASSESSMENTS FOLLOW-UP
18
Follow-up schedule

• 6 weekly 0 to 24 weeks
• 12 weekly up to 2 years
• 6 monthly up to 5 years
• Annually thereafter

19
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

20
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

21
PSA Failure Categories
22
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

23
DRUG SUPPLY
24
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

25
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

26
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

27
CURRENT ACCRUAL
28
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

29
Accrual
30
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) 1535 vs 22 vs 8
High risk newly diagnosed pts n () 1460 (93)
Previously treated/relapsing pts n () 105 (7)
Data from 30-Apr-2010
31
TRIAL COMMITTEESAND CONTACTS
32
Trial Management Group

• Nick James Oncologist CI, Chair, Birmingham, UK
• Noel Clarke Urologist Vice-Chair Manchester, UK
• Malcolm Mason Oncologist Vice-Chair Cardiff, UK
• John Anderson Urologist Sheffield, UK
• David Dearnaley Oncologist Sutton, UK
• John Dwyer Patient representative Stockport, UK
• John Masters Pathologist London, UK
• Rick Popert Oncologist London, UK
• Marc Schulper Health Economist York, UK
• Andrew Stanley Pharmacist Birmingham, UK
• George Thalmann Oncologist Bern, CH
• Elizabeth Clark Data Manager MRC CTU, UK
• Pierre Fustier Trial Coordinator SAKK, CH
• Charlene Griffith Data Manager MRC CTU, UK
• Gordana Jovic Statistician MRC CTU, UK
• Max Parmar Statistician MRC CTU, UK
• Karen Sanders Trial Manager MRC CTU, UK

33
Contact us

• Karen Sanders
• Trial Manager
• MRC Clinical Trials Unit
• T 0207 670 4831
• E stampede_at_ctu.mrc.ac.uk
• Charlene Griffith Liz Clark
• Data Managers
• MRC Clinical Trials Unit
• T 0207 670 4882/4794
• E stampede_at_ctu.mrc.ac.uk