STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Sponsor number: MRC PR08 ISRCTN number: ISRCTN78818544 EUDRACT number: 2004-000193-31 CTA number: 00316/0026/001-0001

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

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

Current comparison Design: Protocol v10

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

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

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

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

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

PATIENT SELECTION CRITERIA

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+

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

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

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

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!

Clarification of HT prior randomisation See Appendix L

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)

TREATMENT ADMINISTRATION

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

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

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

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

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

Radiotherapy

Radiotherapy in STAMPEDE

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

Standard-of-care radiotherapy

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

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

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

Early separation of OS curves 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

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

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

Research (M1) Prostate Radiotherapy

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

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

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

ASSESSMENTS & FOLLOW-UP

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

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

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.

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.

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.

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

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.

DRUG SUPPLY

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

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

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”

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 02076704818)

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

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

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

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

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

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%)

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

Case Report Forms

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

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

Randomisation CRF

Randomisation CRF

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

TRIAL COMMITTEES AND CONTACTS

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

Contact us Web: www.stampedetrial.org MRC Francesca Schiavone Clinical Trial Manager T: +44 (0) 207 670 4632 E: stampede@ctu.mrc.ac.uk Alanna Brown T: +44 (0) 207 670 4882 Dominic Hague, Katie Ward STAMPEDE Data Managers T: +44 (0) 207 670 4809 / 4794 / 4947 66