MRC Clinical Trials Unit STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Sponsor number:MRC PR08 ISRCTN number: ISRCTN EUDRACT number: CTA number: 00316/0026/ How to report Progressions and RT data

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 (Open access)

MRC Clinical Trials Unit Timelines: initial plans ADT-alone A ADT + zoledronic acid B ADT + docetaxel C ADT + celecoxib D ADT + zoledronic acid + docetaxel E ADT + zoledronic acid + celecoxib F Past accrual Possible future accrual Follow-up

MRC Clinical Trials Unit Accrual: end of Activity Stage II ADT-alone A ADT + zoledronic acid B ADT + docetaxel C ADT + celecoxib D ADT + zoledronic acid + docetaxel E ADT + zoledronic acid + celecoxib F Past accrual Possible future accrual Follow-up

MRC Clinical Trials Unit Timelines: from Nov A ADT + zoledronic acid B ADT + docetaxel C ADT + celecoxib D ADT + zoledronic acid + docetaxel E ADT + zoledronic acid + celecoxib F ADT + abiraterone G ADT-alone Past accrual Possible future accrual Follow-up

MRC Clinical Trials Unit Timelines: from Jan A ADT + zoledronic acid B ADT + docetaxel C ADT + celecoxib D ADT + zoledronic acid + docetaxel E ADT + zoledronic acid + celecoxib F ADT + abiraterone G ADT-alone H ADT + RT Past accrual Possible future accrual Follow-up M1 only

MRC Clinical Trials Unit Timelines: from March A ADT + zoledronic acid B ADT + docetaxel C ADT + celecoxib D ADT + zoledronic acid + docetaxel E ADT + zoledronic acid + celecoxib F ADT + abiraterone G ADT-alone H ADT + RT Past accrual Possible future accrual Follow-up M1 only

MRC Clinical Trials Unit Arms recruiting protocol 9.0

MRC Clinical Trials Unit Current comparison Design: Protocol v10

MRC Clinical Trials Unit Main Inclusion Criteria Four broad disease categories: Newly diagnosed high risk T3/4 N0 M0 Newly diagnosed node positive T any N+ M0 Newly diagnosed metastatic T any N any M+ Previously treated now relapsing: PSA  4ng/ml and rising with doubling time < 6 months PSA  20ng/ml N+ M+ Please see protocol section 4.1 and 4.2 for complete details about inclusion and exclusion criteria

MRC Clinical Trials Unit How to report progression events

MRC Clinical Trials Unit STAMPEDE Follow-up schedule 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 6 weekly0 to 24 weeks 12 weeklyup to 2 years 6 monthlyup to 5 years Annuallythereafter

MRC Clinical Trials Unit Assessment of Treatment Failure Types of progression: 1.Biochemical 2.Local 3.Lymph node 4.Distant metastatic 5.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 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

MRC Clinical Trials Unit Defining PSA Relapse 3 PSA failure categories: PSA Failure Category A – When nadir is > 50% baseline (failed at time zero) PSA Failure Category B – Nadir is over 4ng/ml. Relapse occurs when PSA increases by 50% above nadir PSA Failure Category C – Nadir is under 4ng/ml. Relapse occurs when PSA increases by 50% above nadir or above 4ng/ml, whichever is greatest

MRC Clinical Trials Unit Ensure a confirmatory PSA test is done between 1 week and 3 months: if value is ≥ PSA progression value then report biochemical progression If the clinician decides that a patient has biochemically progressed before progression value is met (e.g. by adding anti-androgens): Report progression as normal Defining PSA Relapse

MRC Clinical Trials Unit Progression letters 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 J for details of how to calculate the progression value OR Contact the trial team for help

MRC Clinical Trials Unit PSA Progression categories: examples Progression category Pre-HT PSA (ng/ml) PSA Nadir (ng/ml) PSA progression Value (ng/ml) A (at week 24) B C

MRC Clinical Trials Unit Assessment of Treatment Duration– Arm G For M+ patients, treatment should continue until all progressions occur: 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. All progressions must be reported as per the other arms

MRC Clinical Trials Unit Assessment of Treatment Duration– Arm G For N0M0 patients or N+M0 patients planned for RT treatment should continue until: 2 years or Disease progression as defined for M+ patients, whichever is sooner For patients with N+M0 disease not planned for radical radiotherapy should continue until: Disease progression as defined for M+ patients

MRC Clinical Trials Unit Reporting progressions on CRFs In case of progression, complete and return: Follow up form for the relevant visit (e.g. week 6, 12, 18, 24 etc) Progression and Additional Treatment form End of treatment form (if applicable) Death form (if applicable)

MRC Clinical Trials Unit Reporting progressions on CRFs For patients on Arms A, B, C and E: Please continue to follow up as normal and report data on Follow up (post-progression) form Please ensure that any second-line treatments are reported on the form For patients on Arm G: Please continue to follow up as normal but report data on Follow up form until all types of progression occur Please ensure no further second-line treatment is given until: all types of progressions are reported trial abiraterone treatment is stopped

MRC Clinical Trials Unit Some examples… Follow up form

MRC Clinical Trials Unit Some examples… Progression and Additional Treatment Form

MRC Clinical Trials Unit What to do post-progression Continue to follow up patients as normal until death Complete Follow up (Post-progression) form at each follow up visit Ensure additional treatment post progression are reported using the Additional Treatments form In case of missed follow up, please return the Follow up form as normal indicating “Missed visit“ at the top of the form PSA value (if known) Week number

MRC Clinical Trials Unit How to report RT data

MRC Clinical Trials Unit Radiotherapy in STAMPEDE

MRC Clinical Trials Unit 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 RT given 6 to 9 months after randomisation

MRC Clinical Trials Unit Standard-of-care radiotherapy

MRC Clinical Trials Unit The use of radiotherapy to the prostate will retard progression of the metastases in men presenting with metastatic prostate cancer The primary tumour may be required to stimulate disseminated tumour cells to grow into metastases Supporting evidence in renal and prostate cancer ( SWOG 8949, EORTC 30947, MRC PR07 /NCIC PR.3 trials) Research (M1) Prostate Radiotherapy

MRC Clinical Trials Unit Research (M1) Prostate Radiotherapy

MRC Clinical Trials Unit Reporting radiotherapy data For patients who receive a primary or research course of radiotherapy, complete and return Radiotherapy detail form Radiotherapy acute toxicity form For patients who receive a palliative course of radiotherapy, complete and return Palliative radiotherapy form

MRC Clinical Trials Unit For patients who receive RT, RT detail form should be completed when the patient's course is completed For standard-of-care RT, please ensure forms are completed and returned after a maximum of 12 months post- randomisation For research (M1) RT to prostate please ensure forms are completed and returned after a maximum of 8 weeks post- randomisation For patients who do not receive primary RT, it should be completed 10 months after randomisation to confirm that RT was not given Reporting radiotherapy data

MRC Clinical Trials Unit Some examples… RT detail form

MRC Clinical Trials Unit RT acute toxicity form Some examples…

MRC Clinical Trials Unit Conclusion Ensure Failure Free Survival events (e.g biochemical progression) is reported appropriately Arm-specific rules Treatment duration Follow up continues until death (overall survival) Report RT information: Standard-of-care RT (M0N0 or M0N+) Research RT to prostate (newly diagnosed M+)

MRC Clinical Trials Unit TRIAL COMMITTEES AND CONTACTS

MRC Clinical Trials Unit Trial Management Group Nick JamesOncologist; CI, Chair, Birmingham, UK Noel ClarkeUrologist; Vice-ChairManchester, UK Malcolm MasonOncologist; Vice-ChairCardiff, UK Alastair Ritchie Trial Surgeon MRC CTU David DearnaleyOncologistSutton, UK Chris Parker OncologistSutton, UK Robert MillmanPatient representativeStockport, UK John MastersPathologistLondon, UK Martin RussellOncologist Glasgow, UK Marc SchulperHealth EconomistYork, UK Andrew StanleyPharmacistBirmingham, UK George ThalmannOncologistBern, CH Daniel AebersoldClinical OncologistBern, CH Estelle CassolyTrial CoordinatorSAKK, CH Claire AmosClinical Project ManagerMRC CTU, UK Francesca Schiavone Clinical Trial ManagerMRC CTU, UK Alanna Brown Clinical Trial ManagerMRC CTU, UK Dominic HagueData ManagerMRC CTU, UK Katie WardData ManagerMRC CTU, UK Peter Vaughan Data Manager MRC CTU, UK Melissa SpearsTrial StatisticianMRC CTU, UK Max ParmarCTU DirectorMRC CTU, UK Matthew SydesCTU Lead/Senior Trial StatisticianMRC CTU, UK

MRC Clinical Trials Unit Contact us Web: MRC Francesca Schiavone Clinical Trial Manager T: +44 (0) E: Alanna Brown Clinical Trial Manager T: +44 (0) E: Dominic Hague, Katie Ward, Peter Vaughan STAMPEDE Data Managers T: +44 (0) / 4794 / 4947 E: