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 Sponsor number: MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA number: 00316/0026/001-0001

2. 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.10. 39. http://www.trialsjournal.com/content/10/1/39 (Open access) Design rationale

3. 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 Trial Design Stages

4. Current comparison Design: Protocol v10

5. Past accrual Possible future accrual 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 Follow-up

6. Past accrual Possible future accrual 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 Follow-up

7. Past accrual Possible future accrual 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 G ADT + abiraterone Follow-up

8. Past accrual Possible future accrual 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 G ADT + abiraterone M1 only H ADT + RT Follow-up

9. Past accrual Possible future accrual 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 G ADT + abiraterone M1 only H ADT + RT Follow-up

10. PATIENT SELECTION CRITERIA

11. 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+ Main Inclusion Criteria

12. 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 Inclusion/Exclusion Criteria

13. 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. 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! Hormone Therapy Before Randomisation

16. Clarification of HT prior randomisation See Appendix L

17. 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) Screening Procedures

18. TREATMENT ADMINISTRATION

19. 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 Hormone Therapy

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.

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. 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 Abiraterone: Hepatotoxicity

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

29. Supporting evidence: metastatic renal carcinoma EORTC 30947 SWOG 8949 Flanigan RC et al. NEJM 345(23):1655-9. Mickisch GHJ et al. Lancet 358:966-70.

30. Weckermann JCO 2009; 27(10): 1549-56 Supporting evidence: prostate cancer Post-prostatectomy Pre-prostatectomy Inference: The primary tumour may be required to stimulate disseminated tumour cells to grow into metastases

31. Supporting evidence: SPCG-7 Early separation of OS curves Widmark et al The Lancet 2009 373, 301-308 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. For patients who receive a primary or research course of radiotherapy Radiotherapy detail form Radiotherapy acute toxicity form Radiotherapy

36. 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 Cost of radiotherapy

37. Noadditional 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 Radiotherapy Quality Assurance

38. ASSESSMENTS & FOLLOW-UP

39. 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 Identification and consent

40. 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 Follow-up schedule

41. 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 treatmentupdateform’ if a patient receives additional treatment for a progression that you have already reported. Assessment of Treatment Failure

42. 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. Assessment of Treatment Failure – Arm G

43. 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. Assessment of Treatment Failure – Arm G

44. 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 Defining PSA Nadir & PSA Failure Categories

45. 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 receive their 24 week follow-up form. Alternatively please check appendix K for details of how to calculate the progression value. Defining PSA Relapse

46. DRUG SUPPLY

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

48. 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 Safety Reporting

49. 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” STAMPEDE: Clarifications and Exceptions

50. 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 02076704818) Notifications and responsibilities