Practical Implementation of

1
Practical Implementation of Multi-Arm
Multi-Stage Trials Mahesh Parmar Director MRC
Clinical Trials Unit
2
Structure of presentation

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

3
1. MAMS Designs

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

4
Why Multi-Arm, Multi-Stage trials?

• More often than not new is not better
• Academia
• 624 NCI sponsored phase III trials (Arch. Int
  Med, 2008)
• 30 of trials statistically significant
• 40 of trials new therapy preferred
• Industry
• Agents successful at phase I only 10-20 receive
  a marketing authorisation
• Success rate of phase III trials 30-40

5
Why Multi-Arm, Multi-Stage trials?

• Typical (academic) Phase III trial
• Hundreds or thousands of patients
• 5 to 10 years from idea to result
• Hundreds of research staff
• Cost millions in development
• Years of investment from the key players
• High chance of finding new treatment is not
  superior

6
Principles of a New Strategy

• Need better mechanism
• than single arm phase II trial to decide
• Test as many new promising treatments as possible
  
• in the same timescale
• maximise potential for a positive trial
• Potential to discontinue unpromising arms
• quickly and reliably
• Start to randomise as quickly as possible
• Multi-Arm, Multi-Stage (MAMS) trials

7
Activity (phase II stages)

• Asks the question
• Are there reasons why we should not continue
  testing this treatment?
• Testing for a lack-of-activity
• Emphasis not testing for activity but for
  lack-of-activity or lack-of-sufficient-benefit

8
Activity phase II stages

• Assume definitive outcome measure is most
  clinically relevant
• eg overall survival in cancer trials
• In Activity Stages focus on an earlier outcome
  measure
• eg failure-free survival (FFS) in cancer trials

9
Multi-Arm, Multi-Stage Trials
R A N D O M I S E
Con-trol
Test 1
Test 2
Eligible patient
Test 3
Test 4
10
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
Intermediate analyses 1
R A N D O M I S E
Con-trol
Test 1
Test 2
Eligible patient
Test 3
Test 4
11
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
Intermediate analyses 1
R A N D O M I S E
Con-trol
Yes
Test 1
Yes
Test 2
Eligible patient
Yes
Test 3
Yes
Test 4
Yes
12
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 3 accrual
Stage 2 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Test 1
Sufficient activity
Yes
Test 2
Eligible patient
Yes
Test 3
Yes
Test 4
Yes
13
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Yes
Test 1
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Yes
Test 3
Yes
Test 4
Yes
14
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Yes
Test 1
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
Test 3
Yes
Test 4
Yes
15
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Yes
Test 1
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
Test 3
Yes
Test 4
Yes
16
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Yes
Test 1
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
Test 3
Sufficient activity
Yes
Test 4
Sufficient activity
Yes
17
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Final analyses
Stage 3 accrual
Intermediate analyses 2
R A N D O M I S E
Con-trol
Yes
Control
Yes
Test 1
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
Test 3
Sufficient activity
Yes
Yes
Test 4
Sufficient activity
Yes
Yes
18
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Intermediate analyses 2
Final analyses
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Yes
Control
Test 1
Sufficient activity
Sufficient activity
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
Test 3
Sufficient activity
Yes
Yes
Test 4
Sufficient activity
Yes
Yes
19
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
Final analyses
R A N D O M I S E
Con-trol
Yes
Control
Yes
Control
Yes
Test 1
Sufficient activity
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
Test 3
Sufficient activity
Yes
Yes
Test 4
Sufficient activity
Yes
Yes
20
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Yes
Control
Yes
Test 1
Sufficient activity
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
No
(N/A)
Test 3
Sufficient activity
Yes
Yes
Test 4
Sufficient activity
Yes
Yes
21
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Yes
Control
Yes
Test 1
Sufficient activity
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
No
(N/A)
Test 3
Sufficient activity
Insufficient activity
Yes
Yes
No
Test 4
Sufficient activity
Yes
Yes
22
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Yes
Control
Yes
Test 1
Sufficient activity
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
No
(N/A)
Test 3
Sufficient activity
Insufficient activity
Yes
Yes
No
Test 4
Sufficient activity
Sufficient activity
Yes
Yes
Yes
23
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Control
Yes
Control
Yes
Test 1
Sufficient activity
Primary analysis
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Yes
No
No
(N/A)
Test 3
Sufficient activity
Insufficient activity
Yes
Yes
No
Test 4
Sufficient activity
Sufficient activity
Primary analysis
Yes
Yes
Yes
24
Multi-Arm, Multi-Stage Trials
Stage 1 accrual
Intermediate analyses 1
Final analyses
Stage 2 accrual
Intermediate analyses 2
Stage 3 accrual
R A N D O M I S E
Con-trol
Yes
Control
Control
Yes
Control
Yes
Test 1
Sufficient activity
Primary analysis
Sufficient activity
Yes
Yes
Yes
Test 2
Eligible patient
Insufficient activity
Secondary analysis
Yes
No
No
(N/A)
Test 3
Sufficient activity
Secondary analysis
Insufficient activity
Yes
Yes
No
Test 4
Sufficient activity
Primary analysis
Sufficient activity
Yes
Yes
Yes
25
Advantages of MAMS

• Fewer patients
• Less overall time
• Randomised from the start
• Concurrent (not sequentially)
• No delay between phase II and phase III
• Fewer applications for finance and approvals
• one grant application
• one protocol
• one CTA submission (per country)
• one ethics submission (per country)
• one RD approval (per site)
• Saves many years!

26
Advantages of MAMS

• Fewer patients
• Less overall time
• Increased flexibility
• Reduced costs

27
2. MAMS application in STAMPEDE

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

28
Impact

• Most common male cancer
• UK diagnosis 34,000 in 2005
• UK deaths 10,000 in 2006
• Global deaths 250,000 in 2000
• Rising rates of diagnosis
• Aging population, awareness, PSA screening
• Modest treatment effect big impact

29
Needs in prostate cancer

• Urgent need to improve outcomes for men starting
  hormone therapy with prostate cancer
• Median survival 4 years
• Median failure-free survival 2 years
• No new therapies improving survival for this
  group of men for many years

30
Design rationale

• Many interesting agents
• Different classes and modes of action
• No obvious reason to choose one
• Many used in later stages of disease
• Dont want to choose arbitrarily
• Quicker and efficient to use MAMS design

31
Trial Design
32
Trial Design Stages

• Stage Outcome Measures
• Primary Secondary
• Pilot Safety Feasibility
• Activity I-III Failure-free survival Overall
  survival
• (phase II) (PSA-driven) Toxicity
• Skeletal-related events
• Efficacy IV Overall survival Failure-free
  survival
• (phase III) Toxicity
• Skeletal-related events
• Quality of life

33
Design Assumptions for all stages

• Pairwise comparison of each research arm against
  control
• Hazard ratios for design
• 10 improvement in FFS 50 to 60 at 2 yr

Overall survival Failure-free survival
Null (H0) 1.00 1.00
Alternative (HA) 0.75 0.75
34
Significance level and power
Stage Primary Outcome Significance Level Power
I FFS 0.50 95
II FFS 0.25 95
III FFS 0.10 95
IV OS 0.025 90
Overall - 0.013 85
35
Cutpoints in STAMPEDE
95 power
95 power
95 power
36
3. Issues in implementation

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

37
Groups to convince 1

• Medical community
• Mostly seen by urologists
• Trial treatments need to be given by oncologists
• Would it appear complex in clinics?
• Or in MDT meetings?
• Previous multi-arm trials
• Excellent recruitment to
• FOCUS colorectal cancer 5 arms
• ICON5 ovarian cancer 5 arms

38
Groups to convince 2

• Men with prostate cancer
• Involved patient groups
• Two patients on Trial Management Group
• Very positive opinions
• Patient involvement has been excellent for trial
• Two-part PIS
• General information (few pages) prior to
  randomisation
• Arm-specific information
• All before randomisation or
• Only relevant one after randomisation (few pages)
• Patient choice as informed as patient would
  like to be

39
Groups to convince 3

• Funding bodies
• Regulatory and ethical committees
• Hospital governance
• Potential for conservative reviewers
• No precedent for such approaches
• Approved after a bit of discussion

40
Groups to convince 4

• Industry partners
• 3 industry partners in STAMPEDE
• All keen on design because
• Not primarily comparing their drugs head to head
• Efficient design
• Early get-out if agent not so beneficial
• More companies more negotiations
• More contracts
• More time

41
Recruitment

• How many patients are required?
• Total N dependent on
• Observed accrual rates
• Observed event rates
• Do we have the predicted mix of patients?
• arms recruiting in each Activity Efficacy
  Stage
• Likely 2300 to 3600 patients
• Over 5.5 to 7.5 years
• Faster recruitment
• Requires more patients
• Takes less time

42
STAMPEDE Accrual
43
Pilot Phase

• Assessing safety feasibility
• Particularly for the combination arms
• Target 210 patients in 18 months
• Limited centres
• Completed Oct-2005 to Spring-2007
• On schedule
• IDMC recommended continuing all arms
• None stopped because of clear safety signals

44
Stage 1

• Completed ahead of schedule
• IDMC recommended continuation of all arms

45
Hurdles

1. Funding
2. Finalising choice of drug
3. Discussions with pharma
4. Funding (revisited)
5. EU Clinical Trials Directive
6. Vioxx
7. Increased number of stages
8. Continuity of staff
9. Pilot phase

46
Funding main grant

• Outline Application to MRC May 2001
• Accept for Full Application
• Novel design novel drugs vs conservatism
• Advised to submit to CTAAC instead
• New at time for cancer trials, incl. MRC funds
• Outline Application to CTAAC November 2001
• Accept for Full Application
• Full Application to CTAAC November 2002
• Accepted for partial funding Feb 2003
• Agreements/funding needed from industry partners

47
Funding industry partners

• Novartis zoledronic acid
• Research grant
• Free drug
• Drug distributed to sites
• Sanofi-Aventis docetaxel
• Research grant
• Discounted drug (buy 1, get 2 free)
• Sites to buy drug claim back
• Pfizer celecoxib
• Free drug
• Research grant, including distribution costs

48
Negotiations

• Discussions required in many trials
• More difficult if many companies?
• Different pace
• Different contracts
• Different comments on protocol
• Flagged plans for future discussions
• International expansion planned
• All agreements made with UK affiliates

49
Changes in CTU Personnel
Continuity
3 Project Leads
5 Trial Managers
7 Data Managers
3 Patients/Consumer representatives 3 Patients/Consumer representatives 3 Patients/Consumer representatives
3 Statisticians (including the original 2!) 3 Statisticians (including the original 2!) 3 Statisticians (including the original 2!)




50
Future hurdles

• Recruitment rates
• Contracts revisited
• Moving through MAMS stages
• Dropping arms
• Completing recruitment
• Adding arms

51
5. Issues in intermediate analyses

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

52
Moving through stages

• IDMC review interim data
• Safety and activity data
• Recommendations to TSC and TMG
• Education training
• For all committees
• Trust in relationships
• Hypothetical examples

53
Moving through stages

• Face-to-face meeting between TSC and IDMC
• Discussion of different scenarios
• Agree a lengthy communication plan including
  timelines
• Between IDMC and TSC
• To Centres
• To Participants
• To Regulators
• Changes in randomisation programme etc

54
Dropping arms or agents

• If combination arm stopped for lack of sufficient
  effect
• Should single agent arm stop too?
• If single agent arm stopped for lack of
  sufficient effect
• Should combination arm stop too?
• Training and discussion

55
Adding new arms

• Could an extra arm be added?
• Promising agents could be added later!
• Rolling trial or roundabout design?
• Use same approach as for other arms, but delayed
• Implementing in STAMPEDE
• Considering abiraterone
• Application to CTAAC (CRUK) approved
• Company considering proposal
• Design should be appealing to funders and
  industry
• Pre-existing network of recruiting sites
• Saves 3 years

56
6. Conclusions

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. Conclusions

57
Conclusions

• Multi-arm, multi-stage trials are
• Being done in a number of other cancer types
• Feasible
• Efficient
• Supported by patients, clinicians, funders,
  companies
• STAMPEDE
• Is recruiting well
• Is running well

58
References MAMS trials

• Royston P, Parmar MKB, Qian W
• Novel Designs for Multi-Arm Clinical Trials with
  Survival Outcomes, with an Application in Ovarian
  Cancer. Statistics in Medicine 200322 2239
  2256.
• Barthel FM-S, Royston P, Parmar MKB
• A menu-driven facility for sample size
  calculation in multi-arm, multi-stage randomised
  controlled trials with a survival-time outcome.
  The Stata Journal 2007 (submitted)
• Parmar MKB
• Speeding up the Evaluation of New Agents in
  Cancer. J.Natl.Cancer Inst. 100 (17)1204-1214,
  2008.

59
References - STAMPEDE

• Sydes MR, MKB Parmar, ND James et al
• Issues in applying multi-arm multi-stage (MAMS)
  methodology to a clinical trial in prostate
  cancer the MRC STAMPEDE trial. Trials 10 (39),
  2009.
• James ND, Sydes MR, Clarke NW et al
• STAMPEDE Systemic Therapy for Advancing or
  Metastatic Prostate Cancer -- A Multi-Arm
  Multi-Stage Randomised Controlled Trial. Clinical
  Oncology 20 (8)577-581, 2008.
• James ND, Sydes MR, Clarke NW et al
• Systemic therapy for advancing or metastatic
  prostate cancer (STAMPEDE) a multi-arm,
  multistage randomized controlled trial. BJU.Int
  103 (4)464-469, 2009.

60
Software and wokshop

• Free software available
• Design MAMS trials
• Available from MRC CTU
• Implemented in Stata
• CTU Workshop in February 2011
• Design and analysis of MAMs trials
• Advanced Issues in Design and Analysis of Trials
  with Time to Event Outcomes

61
(No Transcript)
62
Other MAMS trials

• ICON 6
• 3-arm, 4-stage trial in 2nd line ovarian cancer
  using progression-free survival as the
  intermediate outcome measure
• AML 16
• 5-arm, 2-stage trial in acute myeloid leukaemia

63
Conclusions

• MAMS trials are
• Feasible
• Efficient
• Supported by patients, clinicians, companies

64
Contacts

• Matthew Sydes
• E matthew.sydes_at_ctu.mrc.ac.uk
• T 44 (0)20 7670 4798

65
Extra slides
66
Trial Stage - Pilot
Trial Initiation
6 trial arms
Pilot Phase
(Total 210 pts)
Recruit 210 patients
Key IDMC Independent Data Monitoring
Committee FFS Failure Free survival
67
Trial Stage - Efficacy Stage I
Efficacy Stage I
(Total 1200 pts)
Recruit until 113 control arm FFS events
Key IDMC Independent Data Monitoring
Committee FFS Failure Free survival
68
Trial Stage - Efficacy Stage II
Efficacy Stage II
(Total 1800 pts)
Recruit until 216 control arm FFS events
Key IDMC Independent Data Monitoring
Committee FFS Failure Free survival
69
Trial Stage - Efficacy Stage III
Efficacy Stage III
(Total 2300 pts)
Recruit until 334 control arm FFS events
Key IDMC Independent Data Monitoring
Committee FFS Failure Free survival
70
Trial Stage Efficacy Stage IV
Efficacy Stage IV
(Total 3200 pts)
Recruit until 405 control arm deaths
Main Analyses (1) Overall survival in arms
recruiting in Efficacy Stage IV (2) Secondary
outcome measures in arms recruiting in Efficacy
Stage IV (3) All outcome measures in all 6 arms
involved in trial (regardless of when
recruitment stopped)
71
Statistical Issues

• Pair-wise comparison of each research vs control
• Randomisation ratio
• (ABCDEF) 211111
• Two control arm patients for every research arm
  patients
• Efficient for power
• Randomisation centrally
• Computer based algorithm
• Minimisation with an additional random element
• 7 stratification factors for balancing groups

72
A Traditional approach
B MAMS design
Time
Phase II studies of single agent
Phase II studies of single agent
Phase II studies of combinations
Phase III trials of combinations
MAMS Phase II/III trial of combinations
Notes C control arm R1 research arm R1 R2
Research arm R2 R3 research arm R3 Assumes
that single agent studies would be carried out
before combination studies Assumes that phase II
studies require smaller numbers of patients and
so smaller number of centres. Therefore, phase II
studies of different agents may be carried out
concurrently Assumes that phase III trials
require larger numbers of patients and a network
of centres that can only run one trial at a time
therefore, phase III trials of different agents
must be carried out sequentially MAMS design
rolls phase II assessment of combinations into
the same trial as the phase III assessment of
effectiveness
73
Impact of accrual rates
Accrual/ Year Total pts Duration (yrs) Difference in pts Difference in length
350 2960 8.5 -451 20 months
500 3411 6.8 0 0
750 4046 5.4 635 -17 months
Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage
74
Assumptions in STAMPEDE

• Broad eligibility spectrum
• Patients starting hormone therapy
• Newly metastatic
• New locally advanced
• Previously treated relapsing
• Assume more patients are M0 than M1
• Failure-free survival (FFS) median 2 years
• Overall survival (OS) median 4 years

75
Traditional vs MAMS
Traditional Approach
Multi-arm, Multi-stage
A
B
C
A
B
C
Phase II
Phase III
Total
50
450 4300 1400
600650
50700
6001300
501350
6001950
Phase II 50 pts, Phase III 600pts
76
Example
Action?
A
x
Stop A
x
AB
Stop AB
x
B
Stop B
77
Example
Action?
x
Continue A
x
Continue AB
x
Continue B
78
Example
Action?
x
Stop A
x
Stop AB
x
Continue B
Requires exploration and intra-arm comparisons
79
Example
Action?
x
Continue A
x
Continue AB
x
Continue B
80
Example
Action?
x
Continue A
x
Continue AB
x
Continue B
81
Activity phase II stages

• At any time should be more intermediate events
  than definitive events
• eg more FFS events than deaths (OS)
• Therefore, more power for intermediate outcome
  measure at any time
• Design assumes
• To see an effect on OS you have to see an effect
  on FFS
• Just because you see an effect on FFS does not
  mean that you will see an effect on OS

82
Advantages of MAMS

• Fewer patients
• Less overall time

83
Traditional vs MAMS
Traditional Approach
Multi-Arm, Multi-Stage
A
B
C
A
B
C
Phase II
Phase III
Total
50
600650
450 4300 1400
50700
6001300
501350
6001950
Phase II 50 pts, Phase III 600pts
84
Traditional vs MAMS
Traditional Approach
Multi-Arm, Multi-Stage
A
B
C
A
B
C
Phase II
Phase III
Total
50
600650
450 4300 1400
50700
6001300
501350
6001950
Phase II 50 pts, Phase III 600pts
85
Cutpoints in STAMPEDE
95 power
95 power
95 power
86
Cutpoints in STAMPEDE
95 power
95 power
95 power
87
4. General issues in implementation

1. MAMS Designs
2. MAMS application in STAMPEDE
3. Issues in implementation
4. General issues in implementation
5. Issues in intermediate analyses
6. Conclusions

88
No intermediate outcome?

• Design depends on the use of an intermediate
  outcome
• What happens if no such outcome exists?
• Use the primary outcome, earlier in time
• Lack-of-benefit analysis useful anyway
• Applying this to a number of ongoing trials

89
How many arms?

• Could be many arms
• From 2 to 10 or more
• Consider
• Accrual rates
• Rationale for inclusion
• Adjust randomisation ratio

90
Arms to compare

• Different drugs
• Classes of agent
• Combinations of agents
• Same drug
• Dose levels
• Duration
• Initiation time
• Method of administration
• Non-drug therapy

91
Adding new arms

• Could an extra arm be added?
• Promising agents could be added later!
• Rolling trial or roundabout design?
• Use same rules as for other arms, but delayed
• Exploring in STAMPEDE
• Design should be appealing to industry
• Pre-existing network of recruiting sites
• GSK?

92
Stopping for efficacy?

• Stopping rules specified for lack-of-benefit
• No formal stopping rules for efficacy
• Early data looking for sufficient evidence of
  activity to support continued investment
• Could draw in usual conservative early stopping
  guidelines

93
STAMPEDE TMG
Current TMG members Current TMG members Current TMG members
Nick James Karen Sanders
Noel Clarke Rachel Morgan
David Dearnaley Richard Gracie
Max Parmar Jim Stansfeld
Matt Sydes John Dwyer
Malcolm Mason
John Anderson
Rick Popert

94
How long to get here?

• Oct 2000 first discussion
• Nov 2000 first formal meeting
• Oct 2005 first patient randomised
• Why so long?
• Some issues of design ie MAMS-specific issues
• Some issues of collaboration
• Some issues beyond control

95
Hurdles

1. Funding

96
Hurdles

1. Funding
2. Finalising choice of drug

97
Changes in drugs
1st mtg Nov 2000 1st appln May 2001
Hormone therapy Hormone therapy
Mitoxantrone (MTZ) MTZpred
Docetaxel Docetaxel pred
Prednisolone -
Stilboestrol Stilboestrol aspirin
Estramustine Estramustine aspirin
?Bisphosphonates (factorial) ?Bisphosphonates
?Herceptin -
?ECF -
?Strontium -
?Epirubicin -
98
Changes in drugs
1st appln May 2001 2nd appln ???
Hormone therapy Hormone therapy
MTZpred MTZpred OR
Docetaxel pred Docetaxel pred
Stilboestrol aspirin Stilboestrol aspirin OR
Estramustine aspirin Estramustine aspirin
?Bisphosphonates ?Bisphosphonates
?Iressa
?Atrasentan
?Celecoxib

99
Changes in drugs
2nd appln ??? Final appln Nov 2002
Hormone therapy Hormone therapy
MTZpred OR -
Docetaxel pred Docetaxel pred
Stilboestrol aspirin OR -
Estramustine aspirin
?Bisphosphonates Zoledronic acid
?Iressa -
?Atrasentan -
?Celecoxib Celecoxib
Docetaxel zoledronic acid
Celecoxib zoledronic acid

100
Change in population

• Originally new M1 only
• Expand to new M1 new M0
• Expand to new M1 new M0 relapsing

101
Hurdles

1. Funding
2. Finalising choice of drug
3. Discussions with pharma

102
Hurdles

1. Funding
2. Finalising choice of drug
3. Discussions with pharma
4. Funding (revisited)
5. EU Clinical Trials Directive

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EU Clinical Trials Directive

• May 2004
• Many uncertainties over sponsorship
• Application for regulatory approval
• Put in before new system to get CTA-rollover
• Easier in old system?
• Less easy not for old system trials

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Hurdles

1. Funding
2. Finalising choice of drug
3. Discussions with pharma
4. Funding (revisited)
5. EU Clinical Trials Directive
6. Increased number of MAMS stages

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Increased stages

• Planned as two-stage trial (plus Pilot)
• IDMC to meet annually
• Therefore, plan more interim hurdles
• Increased from 2 to 4 stages
• Required new program
• -stage2- to -stagen-
• Revise protocol
• Revised again in Summer 2007
• -stagen- to -nstage-
• Small decrease in number of required events

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Changes in trial personnel
Name Involvement
Nick James TMG (CI)
Noel Clarke TMG
David Dearnaley TMG
Max Parmar TMG
Matt Sydes TMG
Sarah Meredith Moved on
Sharon Naylor Moved on
David Kirk Retired (TSC)
Clare Moynihan Moved on
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1. Recruitment rates
Accrual/ Year Total pts Duration (yrs) Difference in pts Difference in length
350 2960 8.5 -451 20 months
500 3411 6.8 0 0
750 4046 5.4 635 -17 months
Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage Assuming median FFS24m, median OS48m, 6 arms recruiting at each stage
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Key points 1

• For many diseases we have many potential new
  treatments
• Majority are likely to prove no more effective
  than control
• We need to change the question we ask
• How do we improve outcomes as rapidly as possible
  for this disease?

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Key points 2

• Intermediate outcome can be very helpful
• Need not be true surrogate
• Often assume larger effect size on intermediate
  outcome
• MAMS trials speed evaluation of new treatments by
  testing many treatments at the same time and
  using lack of benefit analyses