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 Charlene Green STAMPEDE Clinical Trial Manager Sponsor number: MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA number: 00316/0026/001-0001

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.10. 39. http://www.trialsjournal.com/content/10/1/39 (Open access)

3. Trial Design Control Arm R A N D O M I S E Hormone Therapy (HT):According to local practice A 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 E HT + celecoxib: Recruitment completed in April 2011 D 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 Toxicity Skeletal-related events 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 orTany 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.

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 • 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

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. 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 • To be labelled by the pharmacist using labels provided • 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 Data from 31st December 2011

36. Case Report Forms

37. Case Report Forms Please visit the STAMPEDE trial website to download the CRFs - http://www.stampedetrial.org/centres/information_for_centres/crfs_and_completion_guidelines.aspx

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 COMMITTEESAND 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: www.stampedetrial.org MRC Charlene Green Clinical Trial Manager T: +44 (0) 207 670 4882 E: stampede@ctu.mrc.ac.uk Hannah Gardner, Sara Peres, Dominic Hague STAMPEDE Data Managers T: +44 (0) 207 670 4809 / 4794 / 4947 E: stampede@ctu.mrc.ac.uk