Presentation on theme: "Charlene Green STAMPEDE Clinical Trial Manager"— Presentation transcript:
1 Charlene Green STAMPEDE Clinical Trial Manager STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug EfficacyCharlene GreenSTAMPEDE Clinical Trial ManagerSponsor number: MRC PR08 ISRCTN number: ISRCTN EUDRACT number: CTA number: /0026/
2 Design rationale STAMPEDE uses multi-arm multi-stage methodology MAMS design permits rapid comparison and concurrent testing of treatmentsCurrently using 3 investigational drugsIssues 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)
3 Trial Design R A N D O M I S E B C F G Control Arm Hormone Therapy (HT): According to local practiceHT + zoledronic acid: 4mg 3 weekly for 6 cycles and then 4mg 4 weekly for 2 yearsBHT + docetaxel: 75mg/m2 + Prednisolone bid continuously every 3 weeks for 6 cyclesCHT + zoledronic acid + docetaxel: as aboveHT + celecoxib: Recruitment completed in April 2011HT + zoledronic acid + celecoxib: Recruitment completed in April 2011FHT + abiraterone: 1000mg OD (4 tablets) + Prednisolone 5mg ODG
4 Trial Design Stages Stage Outcome Measures Primary Secondary Pilot Safety FeasibilityActivity I-III Failure-free survival Overall survivalToxicitySkeletal-related eventsEfficacy IV Overall survival Failure-free survivalQuality of life
5 Trial Design UpdateAfter the last interim analysis at the end of March 2011 the Trial Steering Committee decided to stop recruitment to arms D (HT + Celecoxib) and F (HT + Zoledronic Acid + Celecoxib) due to lack of sufficient activity. Arms A, B, C and E were also reviewed and continue unchanged.Arm G was added to the trial on 15th November 2011
7 Main Inclusion Criteria Newly diagnosed high risk patients T3/4 N0 M0 with:At least two of:PSA≥40ng/ml or Gleason sum score 8-10And 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 diseaseStage Tany N+ M0 or Tany Nany M+Previously treated relapsing patients with eitherPSA 4ng/ml and rising with doubling time < 6 monthsPSA 20ng/mlN+M+
8 Inclusion/Exclusion Criteria Histological confirmation of prostate cancerIntention to treat with long term HTWHO PS 0,1 or 2Adequate cardiovascular historyNo major dental extractions planned within next 2 yearsPlease see protocol section 4.1 and 4.2 for complete details about inclusion and exclusion
9 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 randomisationOrchidectomy should be performed no more than 12 weeks before randomisationNo more than 14 weeks of anti-androgens before randomisationPSA measurement MUST be taken before HT treatment starts!
10 Screening Procedures Patients identified CT or MRI of pelvis and abdomenBone ScanChest X-ray and ECGPSA TestWithin 8 Weeks of RandomisationBlood Tests(See protocol section 4.3)
12 Hormone Therapy Three acceptable approaches: Bilateral orchidectomy Total or subcapsularLHRH analoguesUsed according to local practiceProphylactic anti-androgens recommendedAnti-androgen monotherapy not allowed
13 Zoledronic acid Zoledronic acid 4mg 15min IV infusion Every 3 weeks for 6 treatmentsThen every 4 weeksPatients should also receive500mg calcium oral supplement400IU vitamin D oral supplementAvailable as a combination tabletContinues until the soonest of:Maximum of 2 yearsdisease (including PSA) progression
14 Docetaxel Docetaxel 75mg/m2 Day 1 as 1hr IV infusion Max 160mg repeated every 3 weeks for 6 cyclesPatients should also receivePrednisolone 5mg bid daily for 21 days
15 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 5mgTaking 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.15
16 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 weeksIn 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
18 RadiotherapyN0M0 patients: Investigators should give radiotherapy (RT) to patients with N0M0 disease, in accordance with the recent data from the PR07 and SPCG trialsIf there is an intention to omit radiotherapy in patients with N0M0 disease this must be discussed with the MRC CTU before consentN+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 randomisationRecommended type, timing and dose in protocol section 6Intention to use RT stated at randomisationensure no bias towards particular combinations of systemic therapy with radiotherapyRT given 6 to 9 months after randomisationand after any docetaxel toxicity settled
19 Radiotherapy For patients who receive a primary course of radiotherapy Radiotherapy formLate radiotherapy toxicity formTo be completed at 6, 12, 24 and 36 months after the radiotherapy.
21 Follow-up schedule 6 weekly 0 to 24 weeks 12 weekly up to 2 years 6 monthly up to 5 yearsAnnually thereafterFollow-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
22 Assessment of Treatment Failure - Arms A -E Treatment should continue until the end of the course or until disease progression, classed as:BiochemicalLocalLymph nodeDistant metastaticSkeletal related eventEach 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.At treatment failure, patients should stop trial treatment. Follow-up schedule continues the same.
23 Assessment of Treatment Failure – Arm G For M+ patients, treatment should continue until clinical disease progressionPSA 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.
24 Assessment of Treatment Failure – Arm G For N0M0 patients or N+M0 patient undergoing radical radiotherapyTreatment 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 progressionPlease call the trial team if you are unsure about whether a patient should stop taking abiraterone.
25 Defining PSA Nadir & PSA Failure Lowest reported PSA levelBetween randomisation and 24 weeksPSA FailureDepends on baseline PSA measurement and PSA nadir3 possible PSA failure categories, A, B and C
27 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 nadirFor Patients in group C – Relapse occurs when PSA increases by 50% above nadir or goes above 4ng/ml, whichever is greatestPSA 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.
29 Drug Supply & Support Novartis Supplying free Zoledronic Acid Providing an educational grant to support some central workSanofi-AventisProviding an educational grantSupplying Docetaxel at a discounted price of buy 1 get 2 freeJanssenSupplying free Abiraterone
30 Please remember to claim! Drug Supply & SupportDepartment of HealthCentral 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 patientsPlease remember to claim!
31 Drug Ordering and Labelling Zoledronic AcidOrdered by MRC CTU at request from centresTo be labelled by the pharmacist using labels providedDocetaxelOrdered by centre pharmacist directly from Sanofi-AventisGeneric brands of docetaxel are not allowed to be used within the trial. Docetaxel provided by Sanofi-Aventis [Taxotere] MUST be the only type used.AbirateroneOrdered by centre pharmacist directly from B&CPre-labelled with generic and trial-specific labels
33 Current Recruitment Status First patient17th October 2005Accrual targetsPilot Phase target was 210 patientsPilot Phase target achieved in March 2007Overall target approximately 3300 patients(440 OS events on control arm)Observed accrual2789 patients have been randomised23rd January 2012
35 Patient Characteristics Age (years) at randomisation median (quartiles)65 (60-70)PSA (ng/ml) at randomisation median (quartiles)65 (23-187)WHO performance status (0 Vs 1 Vs 2+)2111 vs 589 vs 32Bone mets at randomisation n (%)1419 (52%)RT planned n (%)700 (26%)Type of HT: (LHRH vs bicalutamide vs orchidectomy)2671 vs 50 vs 12Data from 31st December 2011