ninth international workshop on pharmacodynamics of anticancer agents durham sept 2013

Adaptive Study Design Multi-Arm, Multi-Stage trials

Nicholas JamesProfessor 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

STAMPEDE Celecoxib -- ECCO 2011 [LBA20] – N Clarke

MAMS Trial DesignMulti-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 practicalities – Heidelberg 2012 – MR Sydes

Advantages of MAMS trials

1. Fewer patients •Concurrent assessment of agents•Randomise from start•One seamless trial•One protocol Less bureaucracy

2. Less overall time

Multi-arm, Multi-stage

T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III

Traditional Approach

Phase II

Phase III

T1

C T1

T2T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2T3

C T3

T4

C T4



3. Increased flexibility •Adapts to intermediate results•Focus on more promising arms


T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III


Phase II

Phase III

T1

C T1

T2T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2T3

C T3

T4

C T4



4. Reduced costs •Limited resources for trials•Must use fairly and efficiently


T2 T3T1C T4

Phase II

Phase III


T2 T3T1C T4

Phase II

Phase III


Phase II

Phase III

T1

C T1

T2T3

C T3

T4

C T4


Phase II

Phase III

T1T1

C T1

T2T3

C T3

T4

C 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 measuresOutcome Measure

Stage Primary Secondary

Pilot Safety Feasibility

Activity I-III Failure-free survival Overall survival

(phase II) Toxicity / safety

Skeletal events

Efficacy IV Overall survival Failure-free survival

(Phase III) Toxicity / safety

Skeletal events

Quality of life


Trial design

Stage Type 10 OM HRA Power Sig. Critical HR

Control Events

1 Activity FFS 0.75 95% 0.500 1.00 114

2 Activity FFS 0.75 95% 0.250 0.92 215

3 Activity FFS 0.75 95% 0.100 0.89 334

4 Efficacy OS 0.75 90% 0.025 - 400

85% 0.013

FFS: failure-free survivalOM: outcome measureOS: overall survival

Overall (per comparison)

• 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

RANDO

MIS

ATIO

N

AAndrogen Deprivation Therapy

B ADT + Zoledronic Acid

C ADT + Docetaxel

D ADT + Celecoxib

E ADT + ZA + Doc

F ADT + ZA + Cel

Control arm

Treatment detail

Androgen Deprivation Therapy:: Standard hormones :: Given for >3 year

Zoledronic Acid:: 3rd generation bisphosphonate:: IV for 2 years every 3 to 4 weeks

Docetaxel:: Taxane chemotherapy:: IV for 6 cycles over 18 weeks

Celecoxib :: Cox-2 inhibitor:: Oral for 1 year

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

MRC PR08

CRUK/06/019

ISRCTN78818544

NCT00268476

Slides for Kim Chi and NCIC CTG: Oct-2011

Accrual: start

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ADT-aloneA

ADT + zoledronic acidB

ADT + docetaxelC

ADT + celecoxibD

ADT + zoledronic acid + docetaxelE

ADT + zoledronic acid + celecoxibF

Past accrual

Possible future accrual Follow-up

ADT + docetaxel

ADT-alone

ADT + zoledronic acid

ADT + celecoxib

ADT + zoledronic acid + docetaxel

ADT + zoledronic acid + celecoxib

Accrual: end of Pilot Phase

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A

B

C

D

E

F

Past accrual


Feasibility and safety confirmed

STOPPING ARMS WITH INSUFFICIENT ACTIVITY


ADT-alone

ADT + docetaxel

ADT + zoledronic acid

ADT + celecoxib

ADT + zoledronic acid + docetaxel


Accrual: end of Activity Stage I

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A

B

C

D

E

F

Past accrual


All arms complete round 2 of their high jump!


Accrual: end of Activity Stage II

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ADT-aloneA


ADT + docetaxelC

ADT + celecoxibD



Past accrual


Celecoxib fails round 3 of its contest


AS 2 analysis (original arms)

• Data frozen: 01-Feb-2011• IDMC meeting: 31-Mar-2011 • Accrual: 2043 patients total• FFS events: 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

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017


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


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

Composition of arms• Abiraterone added Nov

2011

R

A

N

D

O

M

I

S

E

Androgen suppression (AS)

A

B

C

D

E

Control arm

R

A

N

D

O

M

I

S

E

Hormone Therapy (HT)

A

HT + zoledronic acidB

HT + docetaxelC

D

HT + zoledronic acid + docetaxel

E

Control

HT + abirateroneG


Accrual: from Nov-2011

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

ADT + celecoxibD



ADT + abirateroneG

ADT-alone

Past accrual



Local approvals of new comparison

Ready on act ivat ion Suspended unt il ready

Activ

ation

day

0.0

0.2

0.4

0.6

0.8

1.0

Ppn

site

s re

ady:

R&

D a

ppro

val c

onfir

med

104 98(6) 77(21) 58(19) 47(11) 21(26) 13(8) 13(0) 12(1) 11(1) 7(4) 7(0) 7(0) 7(0) 6(1) 3(3)approval

Sit es needing

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Time (weeks) from notifying sites

Timely R&D approval for new protocol

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!

Accrual nearly seamless

Accrual to new arms

Closure of original arms

Cost

• 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

2 arms

Duration of trial

Trial 1

2 armsTrial 2

2+1 arms

Duration of trial

MAMS trial


Accrual: from autumn 2012

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

ADT + celecoxibD



ADT + abirateroneG

ADT-alone

H ADT + RT

Past accrual


Docetaxel and Zoledronic Acid pass their final high jump round

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

NEWLY DIAGNOSED M1 PATIENTS1

A ADT

G ADT + abiraterone

ALL OTHER PATIENTS2

RANDOMISATION

A ADT

G ADT + abiraterone

H ADT + RT to prostate

RANDOMISATION

Patients eligible for STAMPEDE

WHAT’S THE CONTROL ARM?


Analysis: ZA comparison2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

M1 only ADT + RT

ADT + celecoxib


ADT-alone

• Fully powered: accrued through AS4


Analysis: Docetaxel comparison2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

ADT + RT

ADT + celecoxib


ADT-alone

M1 only



Analysis: Doc + ZA comparison2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

ADT + RT

ADT + celecoxib


ADT-alone

M1 only



Analysis: Celecoxib comparisons2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

ADT + RT

ADT + celecoxib


ADT-alone

M1 only

• Less power: stopped accrual in AS2


Analysis: Abiraterone comparison2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

ADT + RT

ADT + celecoxib


ADT-alone

M1 only

• Recruitment in Efficacy Phase 2


Analysis: M1/RT comparison2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

D


F

ADT + abirateroneG

H

In analysis

Not in analysis

ADT + RT (M1-only)

ADT + celecoxib


ADT-alone (M1-only)

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 simultaneously2. 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: 2239–2256

• Barthel FMS, Royston P, Parmar MKBA 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 alSpeeding 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

ninth international workshop on pharmacodynamics of anticancer agents durham sept 2013

Documents

industry trials

common control arm multistage

overall survivaloverall

trials cheaper

new drugs

initial feasibility

patientsadd new treatments

bn paannual research