STAMPEDESystemic Therapy in Advancing or

Metastatic Prostate cancer: Evaluation of Drug Efficacy

Charlene GreenSTAMPEDE Clinical Trial Manager

Sponsor number: MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA 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/10/1/39 (Open access)

Trial Design

Control Arm

RANDOMISE

Hormone Therapy (HT): According to local practiceA

HT + zoledronic acid: 4mg 3 weekly for 6 cycles and then 4mg 4 weekly for 2 yearsB

HT + docetaxel: 75mg/m2 + Prednisolone bid continuously every 3 weeks for 6 cyclesC

HT + zoledronic acid + docetaxel: as aboveE

HT + celecoxib: Recruitment completed in April 2011D

HT + zoledronic acid + celecoxib: Recruitment completed in April 2011F

HT + abiraterone: 1000mg OD (4 tablets) + Prednisolone 5mg OD G

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

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 15th 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 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+

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)

TREATMENT ADMINISTRATION

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/m2 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

Radiotherapy

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 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 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

Assessment of Treatment Failure - Arms A -E

Treatment should continue until the end of the course or until disease progression, classed as:

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.

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

Group A

Group B

Group C0

20

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Nadir

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l)

0 20 40 60 80 100 120Pre-hormone PSA (ng/ml)

---A: PSA nadir > 50% pre-hormone PSA ---> PSA failure nowB: PSA nadir < 50% pre-hormone PSA but >4ng/ml ---> refer to PSA failure graphC: PSA nadir < 50% pre-hormone PSA and <4ng/ml ---> refer to PSA failure graph

Based on nadir PSA before 24 weeks on trial

Groups for defining late PSA failure

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.

DRUG SUPPLY

• 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

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 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 2789 patients have been randomised 23rd January 2012

Accrual

Pilot phase Activity Stage I Activity Stage II

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Observed Expected

There are many hundreds of successful accrual scenarios for recruitment toSTAMPEDE in the Statistical Design Document. One is shown here.

Cumulative randomisation overall

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 31st December 2011

Case Report Forms

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

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

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 COMMITTEESAND CONTACTS

Trial Management Group

Nick James Oncologist; CI, Chair, Birmingham, UKNoel Clarke Urologist; Vice-Chair Manchester, UKMalcolm Mason Oncologist; Vice-Chair Cardiff, UK

John Anderson Urologist Sheffield, UKDavid Dearnaley Oncologist Sutton, UKJohn Dwyer Patient representative Stockport, UKErika Kuettel Trial Coordinator SAKK, CHJohn Masters Pathologist London, UKMartin Russell Oncologist Glasgow, UKMarc Schulper Health Economist York, UKAndrew Stanley Pharmacist Birmingham, UKGeorge Thalmann Oncologist Bern, CH

Charlene Green Clinical Trial Manager MRC CTU, UK Hannah Gardner Data Manager MRC CTU, UKDominic Hague Data Manager MRC CTU, UKGordana Jovic Statistician MRC CTU, UKMax Parmar Statistician MRC CTU, UKSara Peres Data Manager MRC CTU, UKMatthew Sydes CTU Lead/Trial Statistician MRC CTU, UK

Contact us

Web: www.stampedetrial.org

MRC Charlene Green Clinical Trial ManagerT: +44 (0) 207 670 4882 E: stampede@ctu.mrc.ac.uk

Hannah Gardner, Sara Peres, Dominic HagueSTAMPEDE Data ManagersT: +44 (0) 207 670 4809 / 4794 / 4947 E: stampede@ctu.mrc.ac.uk