Presentation on theme: "STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Charlene Green STAMPEDE Clinical Trial Manager Sponsor."— Presentation transcript:
STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Charlene Green STAMPEDE Clinical Trial Manager Sponsor number:MRC PR08 ISRCTN number: ISRCTN78818544 EUDRACT number: 2004-000193-31 CTA number: 00316/0026/001-0001
Design rationale STAMPEDE uses multi-arm multi-stage methodology MAMS design permits rapid comparison and concurrent testing of treatments Currently using 3 investigational drugs 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/10/1/39http://www.trialsjournal.com/content/10/1/39 (Open access)
Trial Design Control Arm RANDOMISERANDOMISE Hormone Therapy (HT): According to local practice A HT + zoledronic acid: 4mg 3 weekly for 6 cycles and then 4mg 4 weekly for 2 years B HT + docetaxel: 75mg/m 2 + Prednisolone bid continuously every 3 weeks for 6 cycles C HT + zoledronic acid + docetaxel: as above E HT + celecoxib: Recruitment completed in April 2011 D HT + zoledronic acid + celecoxib: Recruitment completed in April 2011 F HT + abiraterone: 1000mg OD (4 tablets) + Prednisolone 5mg OD G
Trial Design Update After 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 15 th November 2011
PATIENT SELECTION CRITERIA
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 T any N+ M0 or Tany N any M+ Previously treated relapsing patients with either PSA 4ng/ml and rising with doubling time < 6 months PSA 20ng/ml N+ M+
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
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 No more than 14 weeks of anti-androgens before randomisation PSA measurement MUST be taken before HT treatment starts!
Screening Procedures Patients identified CT or MRI of pelvis and abdomen Bone Scan Chest X-ray and ECG PSA Test Within 8 Weeks of Randomisation Blood Tests (See protocol section 4.3)
Hormone Therapy Three acceptable approaches: Bilateral orchidectomy Total or subcapsular LHRH analogues Used according to local practice Prophylactic anti-androgens recommended Anti-androgen monotherapy not allowed
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/m 2 Day 1 as 1hr IV infusion Max 160mg repeated every 3 weeks for 6 cycles Patients should also receive Prednisolone 5mg bid daily for 21 days
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.
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
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 and after any docetaxel toxicity settled
Radiotherapy For patients who receive a primary course of radiotherapy Radiotherapy form Late radiotherapy toxicity form To be completed at 6, 12, 24 and 36 months after the radiotherapy.
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 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
Assessment of Treatment Failure - Arms A -E Treatment should continue until the end of the course or until disease progression, classed as: 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. At treatment failure, patients should stop trial treatment. Follow-up schedule continues the same.
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.
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.
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
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 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.
Novartis Supplying free Zoledronic Acid Providing an educational grant to support some central work Sanofi-Aventis Providing an educational grant Supplying Docetaxel at a discounted price of buy 1 get 2 free Janssen Supplying free Abiraterone 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 Please remember to claim!
Drug Ordering and Labelling Zoledronic Acid Ordered by MRC CTU at request from centres To be labelled by the pharmacist using labels provided Docetaxel Ordered by centre pharmacist directly from Sanofi-Aventis To be labelled by the pharmacist using labels provided Generic brands of docetaxel are not allowed to be used within the trial. Docetaxel provided by Sanofi-Aventis [Taxotere] MUST be the only type used. Abiraterone Ordered by centre pharmacist directly from B&C Pre-labelled with generic and trial-specific labels
Current Recruitment Status First patient 17 th 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 2789 patients have been randomised 23 rd January 2012
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 32 Bone mets at randomisation n (%)1419 (52%) RT planned n (%)700 (26%) Type of HT: (LHRH vs bicalutamide vs orchidectomy) 2671 vs 50 vs 12 Data from 31 st December 2011
Case Report Forms
Please visit the STAMPEDE trial website to download the CRFs - http://www.stampedetrial.org/centres/information_for_centres/crfs_and_completion_guid elines.aspx
Prior to randomisation These 4 forms should be filled out prior to randomisation: 1.Bone density risk factor questionnaire 2.Randomisation form 3.Baseline form 4.Cardiovascular form
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
CRF completion timing
TRIAL COMMITTEES AND CONTACTS
Trial Management Group Nick JamesOncologist; CI, Chair, Birmingham, UK Noel ClarkeUrologist; Vice-ChairManchester, UK Malcolm MasonOncologist; Vice-ChairCardiff, UK John AndersonUrologistSheffield, UK David DearnaleyOncologistSutton, UK John DwyerPatient representativeStockport, UK Erika KuettelTrial CoordinatorSAKK, CH John MastersPathologistLondon, UK Martin RussellOncologist Glasgow, UK Marc SchulperHealth EconomistYork, UK Andrew StanleyPharmacistBirmingham, UK George ThalmannOncologistBern, CH Charlene GreenClinical Trial ManagerMRC CTU, UK Hannah GardnerData ManagerMRC CTU, UK Dominic HagueData ManagerMRC CTU, UK Gordana JovicStatisticianMRC CTU, UK Max ParmarStatisticianMRC CTU, UK Sara PeresData ManagerMRC CTU, UK Matthew SydesCTU Lead/Trial StatisticianMRC CTU, UK
Contact us Web: www.stampedetrial.org MRC Charlene Green Clinical Trial Manager T: +44 (0) 207 670 4882 E: firstname.lastname@example.org Hannah Gardner, Sara Peres, Dominic Hague STAMPEDE Data Managers T: +44 (0) 207 670 4809 / 4794 / 4947 E: email@example.com