Transcript Site Initiation Training Slides

STAMPEDE
Systemic Therapy in Advancing or
Metastatic Prostate cancer: Evaluation of
Drug Efficacy
Charlene Green
STAMPEDE Clinical Trial Manager
Sponsor number:
ISRCTN number:
EUDRACT number:
CTA number:
MRC PR08
ISRCTN78818544
2004-000193-31
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
R
A
N
D
O
M
I
S
E
A
Hormone Therapy (HT): According to local practice
Control Arm
B
HT + zoledronic acid: 4mg 3 weekly for 6 cycles and then 4mg 4 weekly for 2 years
C
HT + docetaxel: 75mg/m2 + Prednisolone bid continuously every 3 weeks for 6 cycles
D
HT + celecoxib: Recruitment completed in April 2011
E
HT + zoledronic acid + docetaxel: as above
F
HT + zoledronic acid + celecoxib: Recruitment completed in April 2011
G
HT + abiraterone: 1000mg OD (4 tablets) + Prednisolone 5mg OD
Trial Design Stages
Stage
Pilot
Activity I-III
Efficacy IV
Outcome Measures
Primary
Secondary
Safety
Feasibility
Failure-free survival
Overall survival
Toxicity
Skeletal-related events
Overall survival
Failure-free survival
Toxicity
Skeletal-related events
Quality 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+
Inclusion/Exclusion Criteria

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
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 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.
2.
3.
4.
5.
Biochemical
Local
Lymph node
Distant metastatic
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
Groups for defining late PSA failure
Based on nadir PSA before 24 weeks on trial
80
Group A
60
40
Group B
20
0
Group C
0
20
40
60
80
100
Pre-hormone PSA (ng/ml)
--A: PSA nadir > 50% pre-hormone PSA ---> PSA failure now
B: PSA nadir < 50% pre-hormone PSA but >4ng/ml ---> refer to PSA failure graph
C: PSA nadir < 50% pre-hormone PSA and <4ng/ml ---> refer to PSA failure graph
120
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
Drug Supply & Support
• 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 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
Cumulative randomisation overall
2100
Pilot phase
Activity Stage I
Activity Stage II
1800
1500
1200
900
600
300
Date of randomisation
Observed
Expected
There are many hundreds of successful accrual scenarios for recruitment to
ST AMPEDE in the Statistical Design Document. One is shown here.
Oct 11
Jul 11
Jan 11
Jul 10
Jan 10
Jul 09
Jan 09
Jul 08
Jan 08
Jul 07
Jan 07
Jul 06
Jan 06
Oct 05
0
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+)
Bone mets at randomisation n (%)
RT planned n (%)
Type of HT: (LHRH vs bicalutamide vs orchidectomy)
Data from 31st December 2011
2111 vs 589 vs
32
1419 (52%)
700 (26%)
2671 vs 50 vs
12
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_guid
elines.aspx
Prior to randomisation
These 4 forms should be filled out prior to randomisation:
1.
2.
3.
4.
Bone density risk factor questionnaire
Randomisation form
Baseline form
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 James
Noel Clarke
Malcolm Mason
Oncologist; CI, Chair,
Urologist; Vice-Chair
Oncologist; Vice-Chair
Birmingham, UK
Manchester, UK
Cardiff, UK
John Anderson
David Dearnaley
John Dwyer
Erika Kuettel
John Masters
Martin Russell
Marc Schulper
Andrew Stanley
George Thalmann
Urologist
Oncologist
Patient representative
Trial Coordinator
Pathologist
Oncologist
Health Economist
Pharmacist
Oncologist
Sheffield, UK
Sutton, UK
Stockport, UK
SAKK, CH
London, UK
Glasgow, UK
York, UK
Birmingham, UK
Bern, CH
Charlene Green
Hannah Gardner
Dominic Hague
Gordana Jovic
Max Parmar
Sara Peres
Matthew Sydes
Clinical Trial Manager
Data Manager
Data Manager
Statistician
Statistician
Data Manager
CTU Lead/Trial Statistician
MRC
MRC
MRC
MRC
MRC
MRC
MRC
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
CTU,
UK
UK
UK
UK
UK
UK
UK
Contact us
Web: www.stampedetrial.org
MRC
Charlene Green
Clinical Trial Manager
T: +44 (0) 207 670 4882
E: [email protected]
Hannah Gardner, Sara Peres, Dominic Hague
STAMPEDE Data Managers
T: +44 (0) 207 670 4809 / 4794 / 4947
E: [email protected]