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MRC Clinical Trials Unit
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
MRC Clinical Trials Unit
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)
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Trial Design Stages
Stage Outcome MeasuresPrimary Secondary
Pilot Safety Feasibility
Activity I-III Failure-free survival Overall survivalToxicity
Skeletal-related events
Efficacy IV Overall survival Failure-free survivalToxicity
Skeletal-related eventsQuality of life
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Current comparison Design: Protocol v10
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Timelines: initial plans
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
ADT-aloneA
ADT + zoledronic acidB
ADT + docetaxelC
ADT + celecoxibD
ADT + zoledronic acid + docetaxelE
ADT + zoledronic acid + celecoxibF
Past accrual
Possible future accrual Follow-up
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Accrual: end of Activity Stage II
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
ADT-aloneA
ADT + zoledronic acidB
ADT + docetaxelC
ADT + celecoxibD
ADT + zoledronic acid + docetaxelE
ADT + zoledronic acid + celecoxibF
Past accrual
Possible future accrual Follow-up
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Timelines: from Nov-2011
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT + zoledronic acidB
ADT + docetaxelC
ADT + celecoxibD
ADT + zoledronic acid + docetaxelE
ADT + zoledronic acid + celecoxibF
ADT + abirateroneG
ADT-alone
Past accrual
Possible future accrual Follow-up
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Timelines: from Jan-2013
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT + zoledronic acidB
ADT + docetaxelC
ADT + celecoxibD
ADT + zoledronic acid + docetaxelE
ADT + zoledronic acid + celecoxibF
ADT + abirateroneG
ADT-alone
H ADT + RT
Past accrual
Possible future accrual Follow-up
M1 only
MRC Clinical Trials Unit
Timelines: from March-2013
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
A
ADT + zoledronic acidB
ADT + docetaxelC
ADT + celecoxibD
ADT + zoledronic acid + docetaxelE
ADT + zoledronic acid + celecoxibF
ADT + abirateroneG
ADT-alone
H ADT + RT
Past accrual
Possible future accrual Follow-up
M1 only
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PATIENT SELECTION CRITERIA
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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+
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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
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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
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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
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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!
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Clarification of HT prior randomisation
See Appendix L
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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)
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TREATMENT ADMINISTRATION
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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
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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.
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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
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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
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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
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Radiotherapy
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Radiotherapy in STAMPEDE
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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
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Standard-of-care radiotherapy
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•The use of radiotherapy to the prostate will retard progression of the metastases in men presenting with metastatic prostate cancer
Research radiotherapy: Hypothesis
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Supporting evidence: metastatic renal carcinoma
SWOG 8949 EORTC 30947
Flanigan RC et al. NEJM 345(23):1655-9.Mickisch GHJ et al. Lancet 358:966-70.
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Weckermann JCO 2009; 27(10): 1549-56
Supporting evidence: prostate cancer
Inference: The primary tumour may be required to stimulate disseminated tumour cells to grow into metastases
Pre-prostatectomy Post-prostatectomy
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Widmark et al The Lancet 2009 373, 301-308
Early separation of OS curves
Supporting evidence: SPCG-7
Other relevant trial: UK & Canada: MRC PR07 /NCIC PR.3
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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
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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
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Research (M1) Prostate Radiotherapy
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Radiotherapy
For patients who receive a primary or research course of radiotherapy
• Radiotherapy detail form• Radiotherapy acute toxicity form
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• 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
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• 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
Radiotherapy Quality Assurance
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ASSESSMENTS & FOLLOW-UP
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• 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
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Follow-up schedule
6 weekly 0 to 24 weeks12 weekly up to 2 years 6 monthly up to 5 yearsAnnually 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
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Assessment of Treatment Failure
Types of progression:
1. Biochemical2. Local3. Lymph node4. Distant metastatic5. 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.
MRC Clinical Trials Unit
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.
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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.
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Defining PSA Nadir & PSA Failure Categories
• 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
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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 receive their 24 week follow-up form.
Alternatively please check appendix K for details of how to calculate the progression value.
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DRUG SUPPLY
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• Janssen• Supplying free Abiraterone
• Abiraterone• Ordered by centre pharmacist directly from B&C• Pre-labelled with generic and trial-specific labels
Drug Supply & Support
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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
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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”
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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)
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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
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Associated undesirable effects for RT
See Appendix G for more details on both abiraterone and RT
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STAMPEDE Accrual: May2013
Total recruitment (May2013): 4224 patients
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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
• 3984• 31st January 2013• Record month: Jan 2013 (114
patients recruited)• 120 participating centres; 8 Swiss
centres
MRC Clinical Trials Unit
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
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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%)
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New comparison arm
• TMG considering further new research arm
• Survey sent to sites in early Feb for one possible new comparison: Enzalutamide + Abiraterone
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Case Report Forms
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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
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Prior to randomisation
These 4 forms should be filled out prior to randomisation:
1. Bone density risk factor questionnaire2. Randomisation form3. Baseline form4. Cardiovascular form
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Randomisation CRF
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Randomisation CRF
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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
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TRIAL COMMITTEESAND CONTACTS
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Trial Management Group
Nick James Oncologist; CI, Chair, Birmingham, UKNoel Clarke Urologist; Vice-Chair Manchester, UKMalcolm Mason Oncologist; Vice-Chair Cardiff, UK
Alastair Ritchie Trial Surgeon MRC CTUDavid Dearnaley Oncologist Sutton, UKChris Parker Oncologist Sutton, UKRobert Millman Patient representative Stockport, UKJohn Masters Pathologist London, UKMartin Russell Oncologist Glasgow, UKMarc Schulper Health Economist York, UKAndrew Stanley Pharmacist Birmingham, UKGeorge Thalmann Oncologist Bern, CHDaniel Aebersold Clinical Oncologist Bern, CHEstelle Cassoly Trial Coordinator SAKK, CH
Claire Amos Clinical Project Manager MRC CTU, UKFrancesca Schiavone Clinical Trial Manager MRC CTU, UKAlanna Brown Clinical Trial Manager MRC CTU, UK Dominic Hague Data Manager MRC CTU, UKKatie Ward Data Manager MRC CTU, UKPeter Vaughan Data Manager MRC CTU, UKMelissa Spears Trial Statistician MRC CTU, UKMax Parmar CTU Director MRC CTU, UKMatthew Sydes CTU Lead/Senior Trial Statistician MRC CTU, UK
MRC Clinical Trials Unit
Contact us
Web: www.stampedetrial.org
MRC Francesca Schiavone Clinical Trial ManagerT: +44 (0) 207 670 4632 E: stampede@ctu.mrc.ac.uk
Alanna BrownClinical Trial ManagerT: +44 (0) 207 670 4882 E: stampede@ctu.mrc.ac.uk
Dominic Hague, Katie WardSTAMPEDE Data ManagersT: +44 (0) 207 670 4809 / 4794 / 4947 E: stampede@ctu.mrc.ac.uk