Ninth International Workshop On Pharmacodynamics of Anticancer Agents Durham Sept 2013

Adaptive Study Design Multi-Arm, Multi-Stage trials
Nicholas James Professor of Clinical Oncology University of Birmingham @Prof_Nick_James
Cancer research spending

Half of all drugs in trials are cancer drugs Global cancer drug market risen from $48bn (2008) to $75bn (est 2012) 25 drugs with sales >1bn pa Annual research spend:
pharmaceutical industry $6-8 bn NCI $3.6 bn EU public bodies Eur 1.4 bn
If we are to afford new drugs, we must make trials cheaper and quicker
Research environment
New treatments usually not better than current
About 30 to 40% are positive Both academia and industry
Trials require huge time, effort and cost
Must be a better way to select treatments for efficacy assessments
MAMS Trial Design

Multi-Stage: Are there reasons why we should continue investigating a treatment?
Require sufficiently encouraging activity to continue assessment
Focus away from insufficiently active regimens

Focus limited resources on regimens that may benefit patients
Add new treatments of interest
STAMPEDE Celecoxib -- ECCO 2011 [LBA20] N Clarke
Advantages of MAMS trials

1. Fewer patients 2. Less overall time
Concurrent assessment of agents Randomise from start One seamless trial One protocol Less bureaucracy
Multi-arm, Multi-stage
Traditional Approach T1 Phase II T2 T3 T4
C Phase II
T1
T2 T3 T4
C T1 Phase III C T3 C T4 Phase III
STAMPEDE practicalities Heidelberg 2012 MR Sydes

3. Increased flexibility
Adapts to intermediate results Focus on more promising arms
C Phase II
T1
T2 T3 T4

4. Reduced costs
Limited resources for trials Must use fairly and efficiently
C Phase II
T1
T2 T3 T4
MAMS Trial Design

Multi-Arm: Start randomising from the outset Assess many promising agents simultaneously
Compared to a common control arm
Multi-stage Incorporate interim activity assessments

Phase II type assessments of each research arm
Clinical Setting
Men with metastatic or high-risk non-metastatic prostate cancer Long-term hormone therapy (HT) alone is the standard of care Investigating whether early use of additional therapies can improve overall survival Many interesting agents demand assessment
No clear reason to choose one particular regimen Do not want to choose arbitrarily Want to assess all interesting agents
Focussed on three distinct initial treatments

STAMPEDE outcome measures

Outcome Measure Stage Primary Secondary
Pilot
Activity I-III (phase II)
Safety
Failure-free survival
Feasibility
Overall survival Toxicity / safety Skeletal events
Efficacy IV (Phase III)
Overall survival
Failure-free survival Toxicity / safety Skeletal events Quality of life
Trial design
Stage Type 10 OM HRA Power Sig. Critical HR Control Events
1 2 3 4
Activity Activity Activity Efficacy
FFS FFS FFS OS
0.75 0.75 0.75 0.75
95% 95% 95% 90% 85%
0.500 0.250 0.100 0.025 0.013
1.00 0.92 0.89 -
114 215 334 400
Overall (per comparison)
FFS: failure-free survival OM: outcome measure OS: overall survival
Stop early for lack-of-benefit on intermediate primary OM Stop early for benefit only on definitive primary OM
FEASIBILITY ASSESSMENT
STAMPEDE trial
Launched 2005 Initial feasibility stage:
Would patients accept randomisation between 6 treatment arms? Would clinicians put the time into the study to make it work? Would the chosen treatments be safe?
STAMPEDE original design

A Deprivation
Therapy Androgen Control arm
Treatment detail Androgen Deprivation Therapy :: Standard hormones :: Given for >3 year
Man with high-risk prostate cancer starting long-term hormone therapy
RANDOMISATION
B ADT + Zoledronic Acid C ADT + Docetaxel D ADT + Celecoxib E ADT + ZA + Doc F ADT + ZA + Cel
Zoledronic Acid :: 3rd generation bisphosphonat :: IV for 2 years every 3 to 4 we
Docetaxel :: Taxane chemotherapy :: IV for 6 cycles over 18 weeks Celecoxib :: Cox-2 inhibitor :: Oral MRC for 1 PR08 year
CRUK/06/019 ISRCTN78818544
NCT00268476
Accrual: start
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib
ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib
Past accrual Possible future accrual Follow-up

Slides for Kim Chi and NCIC CTG: Oct-2011
Accrual: end of Pilot Phase

Feasibility and safety confirmed

STOPPING ARMS WITH INSUFFICIENT ACTIVITY
Accrual: end of Activity Stage I

All arms complete round 2 of their high jump!

Accrual: end of Activity Stage II

Celecoxib fails round 3 of its contest

AS 2 analysis (original arms)

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Data frozen: IDMC meeting: Accrual: FFS events:
01-Feb-2011 31-Mar-2011 2043 patients total 209 on control arm (target 215)
IDMC recommended changes: : Stop accrual to 2 arms due to lack-of-benefit

Both celecoxib-containing arms (D and F)
: Remaining arms to continue accrual into their Activity Stage III

Arms B, C and E, plus control arm A
Failure-free Survival
Adjusted HR: 0.94 (95%CI 0.74-1.20)
(1-sided upper 75% upper CI 1.03)
Target HR: 0.924
Unadjusted HR = 0.98
2-year FFS 50% (As predicted)

ADDING NEW AGENTS
Flexibility and extension

Design adapts to include further agents
Can add new research arms during trial
Might see as a new trial within STAMPEDE protocol Must be scientifically compelling case for inclusion
Proposed through Trial Management Group Survey of participants Peer review through original funder (Cancer Research UK)
Principles
First priority is to ongoing research arms
Must not hamper accrual or maturity so must either: 1. Recruit better than predicted overall 2. Wait for arms to have dropped out
Accept that new arm will mature later than original research arms
Need to extend accrual to control arm Only compare patients on new arms to patients recruited contemporaneously to control arm
Criteria for new arms

Existing or pending licence in prostate cancer Deliverable across all (or most) trial centres (Pharmaceutical partner willing to support with drug and distribution costs) Model for introduction Draw up draft agreement with partner organisation(s) Needs clinical leader effectively the CI for the new substudy Apply to CRUK for extension of trial
Advantages?
1. Can start recruiting quicker than a new trial
Updated protocol = simple, substantial amendment Scientific review = amendment
2. Efficient use of volunteers

Patients contribute to more than one comparison Reduce competing trials Seamless accrual: no gaps between trials
3. Efficient use of resources

Much quicker start-up time: Start at full speed Much cheaper than separate trial Get answers more quickly STAMPEDE practicalities
Heidelberg 2012 MR Sydes
Disadvantages?
1. Original research arms could mature whilst new assessment ongoing
Treat like data emerging from an external trial TMG will reacts if needed Update backbone of therapy across arms if required Already done for some M0 patients in STAMPEDE: added RT to ADT following published data from SPCG-7 & MRC PR07/NCIC PR.3
STAMPEDE trial design

A
Composition of arms Abiraterone added Nov 2011
R A N D O M I S E
E C B
Hormone Androgen suppression Therapy (AS) (HT)
Control
Con trol a r m
HT + zoledronic acid
HT + docetaxel
HT + zoledronic acid + docetaxel
HT + G abiraterone
Accrual: from Nov-2011

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + abiraterone

Local approvals of new comparison

Timely R&D approval for new protocol 1.0
Ready on activation Suspended until ready
0.8
New arm switched on for whole trial on set date Sites given ~4 wk notice to gain local approvals 80 sites ready to recruit on activation day!
Activation day
0.6
0.4
0.2
Accrual nearly seamless
0.0 0
Sites needing approval
4 5 6 7 8 9 10 11 12 13 14 15 Time (weeks) from notifying sites
104 (6) 98 (21) 77 (19) 58 (11) 47 (26) 21 (8) 13 (0) 13 (1) 12 (1) 11 (4) 7 (0) 7 (0) 7 (0) 7 (1) 6 (3) 3
Aug 13
O ct 05 Jan 06
J ul 06
Jan 07
J ul 07
Jan 08
J ul 08
Jan 09
J ul 09
Jan 10
J ul 10
Jan 11
J ul 11
Jan 12
J ul 12
Jan 13
Z:\Prostate\Stampede\Data\Accrual\rand_planned.wmf
Accrual to new arms

D ate of randomisation
Accrual to abiraterone comparison

1500
Patients in abir ater one compar ison
1200
900
600
Closure of original arms
O ct 13
Apr 13
300
0
J an 12 J ul 12 J an 13 J ul 13 J an 14 J ul 14 J an 15
D ate of r andomisation
Z:\Prostate\Stampede\Data\Accrual\abi_comparison_accrual.wmf
J ul 13
Cost
Duration of trial Trial 1 2 arms
Trial 2
2 arms Duration of trial
MAMS 2+1 arms trial
Faster set up Lower cost as shared between arms New funder needs to provide red area costs, no cost to original funder for extra trial
Accrual: from autumn 2012

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H
ADT-alone ADT + zoledronic acid ADT + docetaxel ADT + celecoxib
Docetaxel and Zoledronic Acid pass their final high jump round
ADT + abiraterone ADT + RT
ADDING FURTHER NEW AGENTS
Adding a randomisation to a subgroup

Prostate radiotherapy standard of care in locally advanced cases Of unproven benefit but of interest in M1 cases
Patients eligible for STAMPEDE NEWLY DIAGNOSED M1 PATIENTS1 RANDOMISATION A G H ADT ADT + abiraterone ADT + RT to prostate A G ALL OTHER PATIENTS2 RANDOMISATION ADT ADT + abiraterone
WHATS THE CONTROL ARM?
Analysis: ZA comparison
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
In analysis Not in analysis

Fully powered: accrued through AS4
Analysis: Docetaxel comparison

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only

Analysis: Doc + ZA comparison

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
Analysis: Celecoxib comparisons

Less power: stopped accrual in AS2
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
Analysis: Abiraterone comparison

ADT-alone
ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

Recruitment in Efficacy Phase 2
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 A B C D E F G H M1 only
Analysis: M1/RT comparison

ADT-alone (M1-only)
ADT + zoledronic acid ADT + docetaxel ADT + celecoxib

ADT + abiraterone ADT + RT (M1-only)
Recruitment in Feasibility Phase
STAMPEDE trial
One question answered celecoxib probably not of value in prostate cancer Docetaxel and zoledronic acid completed intermediate efficacy tests FFS and OS data are awaited Trial expanded twice to add abiraterone, RT in M1 disease Potentially can add arms indefinitely and use as a programmatic platform
Conclusions
MAMS trials speed evaluation of new treatments by:
1. Testing many treatments simultaneously 2. Using LOB analyses to focus research efforts
Insufficiently active arms can successfully be stopped seamlessly in a MAMS trial Adding new research arms to an ongoing trial is achievable and desirable Addition of arms to subgroups feasible and effective e.g.
Stage Pattern of metastasis Biomarkers none yet tested in Stampede but possible in theory
Refs: MAMS trials

Royston P, Parmar MKB, Qian W
Novel Designs for Multi-Arm Clinical Trials with Survival Outcomes, with an Application in Ovarian Cancer. Statistic Med 2003; 22: 22392256
Barthel FMS, 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 2009; 9 (4): 505-523
Parmar MKB, Barthel F, Sydes MR et al

Speeding up the Evaluation of New Agents in Cancer. J Natl Cancer Inst 2008; 100 (17):1204-1214
Refs: STAMPEDE methods & data

Sydes MR, Parmar MKB, James ND et al Issues in applying multi-arm multi-stage (MAMS) methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 2009; 10 (39) James ND, Sydes MR, Parmar MKB et al Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. The Lancet Oncology 13(5): 549-558 Parker, C et al Prostate radiotherapy for men with metastatic disease: a new comparison in the STAMPEDE trial. BJU Int. 2013; 111(5):697-9 and Clin Onc editorial 2013; 25(5): 318-320
Acknowledgements
Matt Sydes and Max Parmar MRC CTU Noel Clark and Malcolm Mason Study Vice Chairs Funding:
Cancer Research UK (CRUK/016/09) Novartis free drug & educational grant Sanofi-Aventis discounted drug & educational grant Pfizer free drug & educational grant Janssen free drug & educational grant MRC core funding
All clinicians and hospital staff who have supported and continue to support the trial All patients who joined the trial and their families

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Adaptive Study Design Multi-Arm, Multi-Stage trials

Nicholas James Professor of Clinical Oncology University of Birmingham @Prof_Nick_James

Cancer research spending

Trials require huge time, effort and cost

Must be a better way to select treatments for efficacy assessments

MAMS Trial Design

Focus away from insufficiently active regimens

Add new treatments of interest

STAMPEDE Celecoxib -- ECCO 2011 [LBA20] N Clarke

Advantages of MAMS trials

Traditional Approach T1 Phase II T2 T3 T4

C T1 Phase III C T3 C T4 Phase III

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Advantages of MAMS trials

Traditional Approach T1 Phase II T2 T3 T4

C T1 Phase III C T3 C T4 Phase III

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Advantages of MAMS trials

Traditional Approach T1 Phase II T2 T3 T4

C T1 Phase III C T3 C T4 Phase III

STAMPEDE practicalities Heidelberg 2012 MR Sydes

MAMS Trial Design

Multi-stage Incorporate interim activity assessments

Focussed on three distinct initial treatments

STAMPEDE outcome measures

Efficacy IV (Phase III)

Failure-free survival Toxicity / safety Skeletal events Quality of life

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Activity Activity Activity Efficacy

FFS FFS FFS OS

0.75 0.75 0.75 0.75

95% 95% 95% 90% 85%

0.500 0.250 0.100 0.025 0.013

1.00 0.92 0.89 -

114 215 334 400

Overall (per comparison)

FFS: failure-free survival OM: outcome measure OS: overall survival

STAMPEDE original design

Man with high-risk prostate cancer starting long-term hormone therapy

Zoledronic Acid :: 3rd generation bisphosphonat :: IV for 2 years every 3 to 4 we

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Past accrual Possible future accrual Follow-up

Accrual: end of Pilot Phase

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Feasibility and safety confirmed

STOPPING ARMS WITH INSUFFICIENT ACTIVITY

Accrual: end of Activity Stage I

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Past accrual Possible future accrual Follow-up

All arms complete round 2 of their high jump!

Accrual: end of Activity Stage II

ADT + zoledronic acid + docetaxel ADT + zoledronic acid + celecoxib

Celecoxib fails round 3 of its contest

AS 2 analysis (original arms)

Data frozen: IDMC meeting: Accrual: FFS events:

IDMC recommended changes: : Stop accrual to 2 arms due to lack-of-benefit

: Remaining arms to continue accrual into their Activity Stage III

Target HR: 0.924

2-year FFS 50% (As predicted)

ADDING NEW AGENTS

Flexibility and extension

STAMPEDE practicalities Heidelberg 2012 MR Sydes

Criteria for new arms