1. STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy
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 1 investigational drug + research radiotherapy
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 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

4. Current comparison Design: Protocol v10

5. Timelines: initial plans
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017 A
ADT-alone B
ADT + zoledronic acid C
ADT + docetaxel D
ADT + celecoxib E
ADT + zoledronic acid + docetaxel F
ADT + zoledronic acid + celecoxib
Plan to continue recruitment or stop early to arms that are insufficiently active
Past accrual
Possible future accrual
Follow-up

6. Accrual: end of Activity Stage II
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017 A
ADT-alone B
ADT + zoledronic acid C
ADT + docetaxel D
ADT + celecoxib E
ADT + zoledronic acid + docetaxel F
ADT + zoledronic acid + celecoxib
IDMC recommend all two arms stop accrual after Activity Stage II (lack-of-benefit) analysis but others continue
Past accrual
Possible future accrual
Follow-up

7. ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib
Timelines: from Nov-2011
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017 A
ADT-alone B
ADT + zoledronic acid C
ADT + docetaxel D
ADT + celecoxib E
ADT + zoledronic acid + docetaxel F
ADT + zoledronic acid + celecoxib
New comparison introduced G
ADT + abiraterone
Past accrual
Possible future accrual
Follow-up

8. ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib
Timelines: from Jan-2013
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017 A
ADT-alone B
ADT + zoledronic acid C
ADT + docetaxel D
ADT + celecoxib E
ADT + zoledronic acid + docetaxel F
ADT + zoledronic acid + celecoxib
Further plans for new comparisons G
ADT + abiraterone H
M1 only
ADT + RT
Past accrual
Possible future accrual
Follow-up

9. Timelines: from March-2013
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017 A
ADT-alone B
ADT + zoledronic acid C
ADT + docetaxel D
ADT + celecoxib E
ADT + zoledronic acid + docetaxel F
ADT + zoledronic acid + celecoxib
Further plans for new comparisons G
ADT + abiraterone H
M1 only
ADT + RT
Past accrual
Possible future accrual
Follow-up

10. PATIENT SELECTION CRITERIA

11. 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+

12. 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

13. Protocol section 4.3 for more information
Selection criteria for M1/RT comparison
Newly diagnosed prostate cancer
Demonstrable M1 disease
No contraindication to radiotherapy
No previous radical prostatectomy
Meets all other eligibility criteria
Protocol section 4.3 for more information

14. Cardiovascular exclusion criteria
Patients with significant cardiovascular disease such as:
MI less than 6 months prior to randomisation
Arterial thrombotic events less than 6 months prior to randomisation
Clinically significant cardiac failure requiring treatment (NYHA II-IV)
Cerebrovascular disease less than 2 years prior to randomisation
Close cardiovascular monitoring recommended for patients in arm G

15. 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
Patients with bilateral orchidectomy should start treatment within 4 weeks from surgery
No more than 14 weeks of anti-androgens before randomisation
PSA measurement MUST be taken before HT treatment starts!

16. Clarification of HT prior randomisation
See Appendix L

17. Screening Procedures Patients identified
CT or MRI of pelvis and abdomen
Bone Scan (or equivalent imagining)
Chest X-ray (unless chest included in CT)
ECG
PSA Test
Within 8 Weeks of Randomisation
Blood Tests
(See protocol section 4.3)

18. TREATMENT ADMINISTRATION

19. Hormone Therapy Three acceptable approaches: Bilateral orchidectomy
Total or sub-capsular
LHRH agonist or antagonist
Used according to local practice
Prophylactic anti-androgens recommended
Anti-androgen monotherapy is not allowed

20. 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. 20

21. 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

22. Abiraterone: Hepatotoxicity
If ALT > 5x ULN (Grade 3 toxicity) treatment should be withheld.
Following LFT return to baseline or Grade 1 reintroduce at reduced dose (750mg daily). Serum transaminases should be monitored every two weeks for three months & monthly thereafter
If hepatotoxicity recurs after the first dose reduction, treatment discontinued.
For severe hepatotoxicity (ALT ≥20x ULN), treatment should be discontinued & not be reintroduced.
Please refer to appendix G2 of the updated STAMPEDE protocol

23. Contra-indication to abiraterone
Abiraterone inhibits enzymes CYP1A2 and CYP2D6
Interactions with:
Betablockers/cardiac drugs
Antidepressants
Analgesics
Anti-fungal agents
Macrolide antibiotics
Antiviral drugs for HIV infection
Antitubercolosis drugs
Anticonvulsants
See Appendix section G.4.3 for more details

24. Radiotherapy

25. Radiotherapy in STAMPEDE

26. Standard-of-care 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

27. Standard-of-care radiotherapy

28. Research radiotherapy: Hypothesis
The use of radiotherapy to the prostate will retard progression of the metastases in men presenting with metastatic prostate cancer

29. SWOG 8949 EORTC 30947 Supporting evidence: metastatic renal carcinoma
Flanigan RC et al. NEJM 345(23):
Mickisch GHJ et al. Lancet 358:

30. Supporting evidence: prostate cancer
Pre-prostatectomy
Post-prostatectomy
Weckermann JCO 2009; 27(10):
Inference: The primary tumour may be required to stimulate disseminated tumour cells to grow into metastases

31. Early separation of OS curves
Supporting evidence: SPCG-7
Early separation of OS curves
Widmark et al The Lancet ,
Other relevant trial: UK & Canada: MRC PR07 /NCIC PR.3

32. Research (M1) Prostate Radiotherapy
RT schedule chosen by doctor and patient if allocated
RT to start within 4 weeks after randomisation
Conformal RT or Intensity Modulated RT
CTV, PTV, dose constraints in protocol section 6.2.5

33. Research (M1) Prostate Radiotherapy
Selection criteria:
Newly diagnosed prostate cancer
Demonstrable M1 disease (excluding local nodes)
No contraindication to RT (e.g. no previous pelvic RT)
No previous radical prostatectomy

34. Research (M1) Prostate Radiotherapy

35. Radiotherapy
For patients who receive a primary or research course of radiotherapy
Radiotherapy detail form
Radiotherapy acute toxicity form

36. Cost of radiotherapy
No capacity issues raised following survey circulated in Q1 2012
M1/RT schedules as excess treatment cost
1 patient recruited month = 2 patients/year arm H
Should be minimal impact
NCRN adopted trial

37. Radiotherapy Quality Assurance
No additional RTQA in sites that has participated in clinical trials of prostate cancer irradiation
RT01, CHHIP, PIVOTAL, RADICALS
For sites which have not participated in such trials, central review of plans for two non-trial patients
All current STAMPEDE centres in UK delivering RT already have RTQA

38. ASSESSMENTS & FOLLOW-UP

39. Identification and consent
General PIS for all patients
Identify which pt could not be allocated to arm H
Verbally inform pts whether could or could not be allocated to arm H
Record correctly pt disease category on CRF
Arm G patients to be re-consented at first available follow up (patients on treatment only)
Send copy of signed consent form to MRC CTU

40. 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

41. Assessment of Treatment Failure
Types of progression:
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.

42. 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.

43. 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.

44. Defining PSA Nadir & PSA Failure Categories
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

45. Defining PSA Relapse 3 PSA failure categories:
PSA Failure Category A – Failed at time zero
PSA Failure Category B – Relapse occurs when PSA increases by 50% above nadir
PSA Failure Category 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 received their 24 week follow-up form.
Alternatively please check appendix K for details of how to calculate the progression value.

46. DRUG SUPPLY

47. Drug Supply & Support Janssen Supplying free Abiraterone Abiraterone
Ordered by centre pharmacist directly from B&C
Pre-labelled with generic and trial-specific labels

48. Safety Reporting
ICH GCP Safety Reporting definitions apply to STAMPEDE
Protocol section 11: Events Terms and Definitions
Definition of an event depends on four factors:
Seriousness
was the event serious?
Any adverse event or reaction that:
Results in death
Is life-threatening
Requires hospitalisation or prolongation of existing hospitalisation
Consist of a congenital anomaly or birth defect
Other important medical condition
Causality
was it related to the trial treatment?
Expectedness
were the symptoms recognised side-effects of the treatment?
NOT ‘we didn’t expect that to happen!’
use List of Expected Toxicities

49. STAMPEDE: Clarifications and Exceptions
The term “life threatening” refers to an event in which the patient was at risk of death at the time of the event
Hospitalisation is defined as an inpatient admission; hospitalisation of pre-existing conditions do not constitute an SAE
Pregnancy occurring in a STAMPEDE patient’s partner must be reported to the MRC CTU within the same timelines as an SAE and classified as “other important medical condition”

50. Notifications and responsibilities
Investigators must notify the MRC CTU of all SAEs from the time of randomisation until 30 days after the last protocol treatment
SAEs in Arm A patients must be reported until 2 years and 2 months or progression
SARs and SUSARs must be notified indefinitely
Causality, expectedness and seriousness should be assessed by a clinician responsible for the care of the patient
SAEs must be notified using the appropriate SAE form by fax (fax number )

51. Trial specific exemptions
Disease progression
Death as result of disease progression
Elective hospitalisation and surgery for treatment of locally advanced or metastatic cancer or its complications
Elective hospitalisation for pre-existing conditions that have not been exacerbated by trial treatment
Elective hospitalisation for pre-existing conditions to simplify treatment or procedures

52. See Appendix G for more details on both abiraterone and RT
Associated undesirable effects for RT
See Appendix G for more details on both abiraterone and RT

53. STAMPEDE Accrual: July 2013
Total recruitment (July 2013): 4500 patients

54. 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
4500 patients
Record month: July 2013 (159 patients recruited)
123 participating centres; 8 Swiss centres

55. Patient Characteristics
Age (years) at randomisation median (quartiles)
65 (37-94)
PSA (ng/ml) at randomisation median (quartiles)
65 (23-188)
WHO performance status (0 Vs 1 Vs 2+)
3193 vs 858 vs 46
Bone mets at randomisation n (%)
2150 (52%)
RT planned n (%)
1189 (29%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
4019 vs 54 vs 19
Data from April 2013

56. Patient characteristics
Newly diagnosed M1
61%
Newly diagnosed N+M0
21%
Newly diagnosed N0M0
14%
Previously treated 3%
Bone mets at randomisation
2,150 (52%)
Liver mets at randomisation
61 (1.5%)
Lung mets at randomisation
104 (3%)
Distant node mets at randomisation
761 (19%)
Other mets at randomisation
173 (4%)

57. New comparison arm TMG considering further new research arm
Survey sent to sites in early Feb for one possible new comparison: Enzalutamide + Abiraterone

58. Case Report Forms

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

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

61. Randomisation CRF

62. Randomisation CRF

63. 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

64. TRIAL COMMITTEES AND CONTACTS

65. Trial Management Group
Nick James Oncologist; CI, Chair, Birmingham, UK
Noel Clarke Urologist; Vice-Chair Manchester, UK
Malcolm Mason Oncologist; Vice-Chair Cardiff, UK
Alastair Ritchie Trial Surgeon MRC CTU
David Dearnaley Oncologist Sutton, UK
Chris Parker Oncologist Sutton, UK
Robert Millman Patient representative Stockport, UK
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
Daniel Aebersold Clinical Oncologist Bern, CH
Estelle Cassoly Trial Coordinator SAKK, CH
Claire Amos Clinical Project Manager MRC CTU, UK
Francesca Schiavone Clinical Trial Manager MRC CTU, UK
Alanna Brown Clinical Trial Manager MRC CTU, UK
Dominic Hague Data Manager MRC CTU, UK
Katie Ward Data Manager MRC CTU, UK
Peter Vaughan Data Manager MRC CTU, UK
Melissa Spears Trial Statistician MRC CTU, UK
Max Parmar CTU Director MRC CTU, UK
Matthew Sydes CTU Lead/Senior Trial Statistician MRC CTU, UK

66. Contact us
Web:
MRC
Francesca Schiavone
Clinical Trial Manager
T: +44 (0) E:
Alanna Brown
T: +44 (0)
Dominic Hague, Katie Ward
STAMPEDE Data Managers
T: +44 (0) / 4794 / 4947 66