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

TRIAL DESIGN

Design rationale STAMPEDE is 6-arm, 5-stage randomised controlled trial 3 investigational drugs Using Multi-Arm Multi-Stage methodology MAMS design MAMS design permits rapid comparison and concurrent testing of treatments

Trial Design

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

PATIENT SELECTION CRITERIA

Main Inclusion Criteria Newly diagnosed high risk patients with one of Any 2 out of the following 3 Stage T3/4 N0 M0 PSA  40ng/ml Gleason sum score 8-10 Stage Tany N+ M0 or Tany Nany M+ Multiple sclerotic bone metastases with a PSA  100ng/ml Previously treated relapsing patients with either PSA  4ng/ml and rising with doubling time less than 6 months PSA  20ng/ml N+ M+

Inclusion/Exclusion Criteria 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

Hormone Therapy Before Randomisation It is preferable that patients are not started on hormones prior to randomisation No more than 12 weeks before PSA measurement taken before HT treatment

Screening Procedures Patients identifed CT or MRI of pelvis and abdomen Bone Scan Chest X-ray and ECG PSA Test Within 8 Weeks of Randomisation Blood Tests

TREATMENT ADMINISTRATION

Hormone Therapy Three acceptable approaches: Bilateral orchidectomy Total or subcapsular LHRH analogues Used according to local practice Prophylactic anti-androgens recommended Anti-Androgens M0 patients only Monotherapy according to local practice

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

Docetaxel Docetaxel 75mg/m2 Patients should also receive Continues: Day 1 as 1hr IV infusion Max 160mg Patients should also receive Prednisolone 5mg bid daily for 21 days Continues: Cycle repeated every 3 weeks for 6 cycles

Celecoxib Celecoxib 400mg Continues until the soonest of: bid Maximum of 1 year Disease (including PSA) progression

Radiotherapy Radiotherapy permitted for suitable patients 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

ASSESSMENTS & FOLLOW-UP

Follow-up schedule 6 weekly 0 to 24 weeks 12 weekly up to 2 years 6 monthly up to 5 years Annually thereafter

Assessment of Treatment Failure New lesions CT scan Increase in baseline lesions Biochemical Rate of fall of PSA and the level of the PSA nadir PSA nadir will be sent to responsible clinician confirming the PSA level which would be taken as progression. Death from prostate cancer

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

PSA Failure Categories

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

DRUG SUPPLY

Drug Supply & Support Novartis Pfizer Sanofi-Aventis Supplying free Zoledronic Acid Providing an educational grant to support some central work Pfizer Supplying free Celecoxib Providing funds to distribute drug to centres Sanofi-Aventis Providing an educational grant Supplying Docetaxel at a discounted price of buy 1 get 2 free

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

Drug Ordering and Labelled Celecoxib and Zoledronic Acid Ordered by MRC CTU at accreditation and on subsequent request from centres Docetaxel Ordered by centre pharmacist All drugs To be labelled by the pharmacist using labels provided

CURRENT ACCRUAL

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 2114 patients have been randomised 28th February 2011

Accrual

Patient Characteristics Age (years) at randomisation median (quartiles) 65 (60-70) PSA (ng/ml) at randomisation median (quartiles) 66 (23-183) WHO performance status (0 Vs 1 Vs 2+) 1628 vs 460 vs 25 Bone mets at randomisation n (%) 1080 (51%) RT planned n (%) 521 (25%) Type of HT: (LHRH vs bicalutamide vs orchidectomy) 2069 vs 35 vs 10 High risk newly diagnosed pts n (%) 1975 (93%) Previously treated/relapsing pts n (%) 139 (7%) Data from 28th Feb 2011

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 John Anderson Urologist Sheffield, UK David Dearnaley Oncologist Sutton, UK John Dwyer 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 Charlene Green Data Manager MRC CTU, UK Gordana Jovic Statistician MRC CTU, UK Erika Kuettel Trial Coordinator SAKK, CH Max Parmar Statistician MRC CTU, UK Tom Fairfield Trial Manager MRC CTU, UK Matthew Sydes CTU Lead/Trial Statistician MRC CTU, UK

Contact us Tom Fairfield Trial Manager MRC Clinical Trials Unit E: stampede@ctu.mrc.ac.uk Charlene Green Data Manager T: 0207 670 4882