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STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Tom Fairfield STAMPEDE Trial Manager Sponsor number: ISRCTN number: EUDRACT number: CTA number: MRC PR08 ISRCTN78818544 2004-000193-31 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 A Hormone therapy (HT) alone B HT + zoledronic acid C HT + docetaxel D HT + celecoxib E HT + zoledronic acid + docetaxel F HT + zoledronic acid + celecoxib R A N D Eligible patient with prostate cancer O M I S E Control Trial Design Stages Stage Pilot Activity I-III Efficacy IV Outcome Measures Primary Secondary Safety Feasibility Failure-free survival Overall survival Toxicity Skeletal-related events Overall survival Failure-free survival Toxicity Skeletal-related events 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 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 bid • Continues until the soonest of: 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 CT scan • 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 • 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 PSA Failure Categories Groups for defining late PSA failure Based on nadir PSA before 24 weeks on trial 80 Group A 60 40 Group B 20 0 Group C 0 20 40 60 80 100 Pre-hormone PSA (ng/ml) --A: PSA nadir > 50% pre-hormone PSA ---> PSA failure now B: PSA nadir < 50% pre-hormone PSA but >4ng/ml ---> refer to PSA failure graph C: PSA nadir < 50% pre-hormone PSA and <4ng/ml ---> refer to PSA failure graph 120 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 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+) Bone mets at randomisation n (%) RT planned n (%) Type of HT: (LHRH vs bicalutamide vs orchidectomy) High risk newly diagnosed pts n (%) Previously treated/relapsing pts n (%) Data from 28th Feb 2011 1628 vs 460 vs 25 1080 (51%) 521 (25%) 2069 vs 35 vs 10 1975 (93%) 139 (7%) TRIAL COMMITTEES AND CONTACTS Trial Management Group Nick James Noel Clarke Malcolm Mason Oncologist; CI, Chair, Urologist; Vice-Chair Oncologist; Vice-Chair Birmingham, UK Manchester, UK Cardiff, UK John Anderson David Dearnaley John Dwyer John Masters Martin Russell Marc Schulper Andrew Stanley George Thalmann Urologist Oncologist Patient representative Pathologist Oncologist Health Economist Pharmacist Oncologist Sheffield, UK Sutton, UK Stockport, UK London, UK Glasgow, UK York, UK Birmingham, UK Bern, CH Charlene Green Gordana Jovic Erika Kuettel Max Parmar Tom Fairfield Matthew Sydes Data Manager Statistician Trial Coordinator Statistician Trial Manager CTU Lead/Trial Statistician MRC CTU, MRC CTU, SAKK, CH MRC CTU, MRC CTU, MRC CTU, UK UK UK UK UK Contact us Tom Fairfield Trial Manager MRC Clinical Trials Unit T: 0207 670 4831 E: [email protected] Charlene Green Data Manager MRC Clinical Trials Unit T: 0207 670 4882 E: [email protected]