1. Charlene Green STAMPEDE Clinical Trial Manager
STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy
Charlene Green
STAMPEDE Clinical Trial Manager
Sponsor number: MRC PR08 ISRCTN number: ISRCTN EUDRACT number: CTA number: /0026/

2. Design rationale STAMPEDE uses multi-arm multi-stage methodology
MAMS design permits rapid comparison and concurrent testing of treatments
Currently using 3 investigational drugs
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
(Open access)

3. Trial Design R A N D O M I S E B C F G Control Arm
Hormone Therapy (HT): According to local practice
HT + zoledronic acid: 4mg 3 weekly for 6 cycles and then 4mg 4 weekly for 2 years B
HT + docetaxel: 75mg/m2 + Prednisolone bid continuously every 3 weeks for 6 cycles C
HT + zoledronic acid + docetaxel: as above
HT + celecoxib: Recruitment completed in April 2011
HT + zoledronic acid + celecoxib: Recruitment completed in April 2011 F
HT + abiraterone: 1000mg OD (4 tablets) + Prednisolone 5mg OD G

4. 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
Quality of life

5. Trial Design Update
After the last interim analysis at the end of March 2011 the Trial Steering Committee decided to stop recruitment to arms D (HT + Celecoxib) and F (HT + Zoledronic Acid + Celecoxib) due to lack of sufficient activity. Arms A, B, C and E were also reviewed and continue unchanged.
Arm G was added to the trial on 15th November 2011

6. PATIENT SELECTION CRITERIA

7. 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+

8. 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

9. 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
No more than 14 weeks of anti-androgens before randomisation
PSA measurement MUST be taken before HT treatment starts!

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
(See protocol section 4.3)

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-androgen monotherapy not allowed

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
repeated every 3 weeks for 6 cycles
Patients should also receive
Prednisolone 5mg bid daily for 21 days

15. 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. 15

16. 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

17. Radiotherapy

18. 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
and after any docetaxel toxicity settled

19. Radiotherapy For patients who receive a primary course of radiotherapy
Radiotherapy form
Late radiotherapy toxicity form
To be completed at 6, 12, 24 and 36 months after the radiotherapy.

20. ASSESSMENTS & FOLLOW-UP

21. 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

22. Assessment of Treatment Failure - Arms A -E
Treatment should continue until the end of the course or until disease progression, classed as:
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.
At treatment failure, patients should stop trial treatment. Follow-up schedule continues the same.

23. 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.

24. 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.

25. Defining PSA Nadir & PSA Failure
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

26. PSA Failure Categories

27. 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
PSA progression letters are sent out every 3 months for patients whom we have receive their 24 week follow-up form.
Alternatively please check appendix K for details of how to calculate the progression value.

28. DRUG SUPPLY

29. Drug Supply & Support Novartis Supplying free Zoledronic Acid
Providing an educational grant to support some central work
Sanofi-Aventis
Providing an educational grant
Supplying Docetaxel at a discounted price of buy 1 get 2 free
Janssen
Supplying free Abiraterone

30. Please remember to claim!
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
Please remember to claim!

31. Drug Ordering and Labelling
Zoledronic Acid
Ordered by MRC CTU at request from centres
To be labelled by the pharmacist using labels provided
Docetaxel
Ordered by centre pharmacist directly from Sanofi-Aventis
Generic brands of docetaxel are not allowed to be used within the trial. Docetaxel provided by Sanofi-Aventis [Taxotere] MUST be the only type used.
Abiraterone
Ordered by centre pharmacist directly from B&C
Pre-labelled with generic and trial-specific labels

32. CURRENT ACCRUAL

33. 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
2789 patients have been randomised
23rd January 2012

34. Accrual

35. Patient Characteristics
Age (years) at randomisation median (quartiles)
65 (60-70)
PSA (ng/ml) at randomisation median (quartiles)
65 (23-187)
WHO performance status (0 Vs 1 Vs 2+)
2111 vs 589 vs 32
Bone mets at randomisation n (%)
1419 (52%)
RT planned n (%)
700 (26%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
2671 vs 50 vs 12
Data from 31st December 2011

36. Case Report Forms

37. Case Report Forms
Please visit the STAMPEDE trial website to download the CRFs -

38. Prior to randomisation
These 4 forms should be filled out prior to randomisation:
Bone density risk factor questionnaire
Randomisation form
Baseline form
Cardiovascular form

39. 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

40. CRF completion timing

41. TRIAL COMMITTEES AND CONTACTS

42. 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
Erika Kuettel Trial Coordinator SAKK, CH
John Masters Pathologist London, UK
Martin Russell Oncologist Glasgow, UK
Marc Schulper Health Economist York, UK
Andrew Stanley Pharmacist Birmingham, UK
George Thalmann Oncologist Bern, CH
Charlene Green Clinical Trial Manager MRC CTU, UK
Hannah Gardner Data Manager MRC CTU, UK
Dominic Hague Data Manager MRC CTU, UK
Gordana Jovic Statistician MRC CTU, UK
Max Parmar Statistician MRC CTU, UK
Sara Peres Data Manager MRC CTU, UK
Matthew Sydes CTU Lead/Trial Statistician MRC CTU, UK

43. Contact us
Web:
MRC
Charlene Green
Clinical Trial Manager
T: +44 (0) E:
Hannah Gardner, Sara Peres, Dominic Hague
STAMPEDE Data Managers
T: +44 (0) / 4794 / 4947 43