CMLSPIRIT 3

Steve O’BrienNorthern Institute for Cancer

Research Newcastle University Medical School

Newcastle, March 2013

www.spirit-cml.org

Imatinibvs

Dasatinib

Thank you!

Acknowledgements

• Randomised open label study3 treatment arms

• Arm A: 400mg daily imatinib• Arm B: 800mg daily imatinib• Arm C: 400mg daily imatinib plus 180mg weekly PEGinterferon

Primary endpoint To compare overall survival in the three arms at 5 yearsN=259

SPIRIT 1 study design

Chronic phase CMLWithin 3 months of

diagnosis

Arm A: Imatinib 400

Arm B: Imatinib 800

Arm C: Imatinib 400 + IFN

R

Imatinib: SPIRIT 1 and trials like it

• 10 year survival >85%• More imatinib isn’t any better• Adding interferon…

– Seems better (France)– Not so sure (Germany)– No difference in survival

• UK doesn’t like interferon

SPIRIT in France: IFN stays the distance

Preudhomme al., New England Journal of Medicine, 2010

REPONSE % (CI 95 %)

Imatinib 400 mg

(N = 159)

Imatinib 600 mg

(N = 160)

Imatinib +

Cytarabine(N = 158)

Imatinib + Peg-IFN(N = 159)

P (P ajusted on Sokal score )

CHR 89 (83-93) 89 (83-93) 95 (90-98 ) 91(87-96) ns

CCR at 6 months at 12 months

50 (42-58 )58 (50-66 )

69 (61-76)65 (57-72)

59 (51-67)70 (62-77)

57 (49-65)66 (58-73)

0,0069 (0,0050)ns

At 12 months MMR SMR

38 (30-46)14 ( 9-21 )

49 (41-57 )17 ( 11-24 )

46 (38-54 )15 ( 10-22 )

57 ( 49-65 )30 ( 23-37 )

0,0063 (0,0048)0,0014 (0,0011)

At 24 months MMR SMR

43 ( 35-50)21 (15-28)

53 (45-60)26 (20-34)

54 (46-62)26 (19-34 )

64 (56-71)38 (30-46 )

0,0063 (0,0032)0,0014 (0,0066)

At 24 months

Undetectable transcript

9 (5-14) 8 (4-13) 8 (4-13 ) 16 (12-24 ) 0,0132 (0,0134)

SPIRIT 2: Study Design

Chronic phase CML

within 3 months of diagnosis

Arm AImatinib 400

Arm BDasatinib 100

Randomised open label studyPrimary endpoint: 5 year EFSSecondary: cyto, molec response, tox

810 of 810 patients recruited!246 since last year

172 sites currently participating

136 sites have recruited41 more than last year

not quite…

So where are we now?

• Most CML patients are fine– There are more and more…

• Not much difference between TKIs?– Apart from cost and perhaps side effects– Use wisely/selectively– Imatinib off patent 2016

• We really need to figure out how to reduce and/or stop treatment for a lot more patients

CML in 2013

(cost)(cost)

Greatestbenefit

Greatestbenefit

Side effectsQoL

Side effectsQoL

EfficacyEfficacy

SPIRIT 3

A Phase III Randomized Trial to Evaluate the Most Effective Way to Use Imatinib, Nilotinib,

and Ponatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

UK National Cancer Research Institute CML Working Group

Prof Stephen O’Brien, Newcastle University

Stage 1

Compare first line intervention

Randomised

Stage 2

Identify partial responders

early

Switch

Stage 3

Identify ‘best’ responders later

Reduce/stop

Primary endpoint: MR3 (MMR) at 3 years

Secondary: sustained MR3

CMR on reduced dose/stop(no more bone marrows!)

EFS, PFS, OSHealth Economics, QoL

SPIRIT 3Newly diagnosed

Stage 1

Compare first line intervention

Randomised

Stage 1: up front randomisation

NilotinibNilotinib

RR

ImatinibImatinib

1000 patients

BCR-ABL (IS) n 5Y-OS

≤1% 218 97%

1-10% 283 94%

>10% 191 87%

Overall Survival (OS)BCR-ABL (IS) at 3 months ≤1% vs. 1-10% vs. >10%

n.s.

0.012

p-value

≤1%1-10%

>10%

Hanfstein et al.Leukemia. 2012 Mar 26. doi: 10.1038/leu.2012.85. [Epub ahead of print]

Stage 2: nilotinib/ponatinib? for >10% @ 3 months

Imatinib >10% PCR~25% patients

Imatinib >10% PCR~25% patients

Nilotinib >10% PCR~10% patients

Nilotinib >10% PCR~10% patients

Stay in SPIRIT 3Switch to ponatinib

Stay in SPIRIT 3Switch to ponatinib

A

B

NilotinibNilotinib

PonatinibPonatinib

NilotinibNilotinib

ImatinibImatinib ImatinibImatinib

PonatinibPonatinib

Comparison

Primary objective

To determine whether, in terms of major molecular response (MMR, MR3) at three years, first-line treatment with imatinib is non inferior to first-line treatment with nilotinib when patients on either treatment who are not responding optimally at 3 and 12 months are ‘rescued’ with ponatinib.

Primary endpoint

• Rate of MR3 at 3 years in groups A & B

• Is group A non-inferior to group B?

Stage 3

Identify ‘best’ responders later

Reduce/stop

How much is enough?

Minimum of 3 years:Halve dose if MMR for 1 year

Minimum of 4 years: Stop if remain in MMR

Primary endpoint: MR3 (MMR) at 3 years

Secondary: sustained MR3

CMR on reduced dose/stop(no bone marrows)

EFS, PFS, OSHealth Economics, QoL

(DESTINY pilot)

Stage 1

Compare first line intervention

Randomised

Stage 2

Identify partial responders

early

Switch

Stage 3

Identify ‘best’ responders later

Reduce/stop

SPIRIT 32013

Patients’ views

• What do you think about SPIRIT 3?

• Home care

• Keeping you informed

SPIRIT 3 arrangements• Design: NCRI CML Working Group• Sponsor: Newcastle Hospitals NHS Trust• Funder: Ariad• NCRI badged, CTAAC approved 2012• Trial management: Newcastle CTU• Governance: TMG, TSC, DMEC• Drug supply:

– Imatinib & nilotinib – NHS, home delivery, VAT– Ponatinib – free of charge for 10 years, home delivery

SPIRIT 3 practicalities• No more marrows

– Unless you want/need to

• PCR essential, especially 3 months and stage 3• Check BP regularly, CV risk• Home delivery, no hospital pharmacy stock

– Pharmacy clinical check

• Biobanking material– Blood and mouthwash

• More direct patient & investigator involvement– Web, apps, meetings

SPIRIT 3 translational research• UK wide collaboration

– Newcastle, Liverpool, Glasgow, Edinburgh, Imperial, Kings

• Comprehensive biobanking– Leukaemia, ‘normal’ tissue

• Factors predicting response, outcome, ability to reduce/stop

• Stem cell biology, NGS (WGS, ES), PCR, TKD mutations, PK

Home care

Stage 1

Compare first line intervention

Randomised

Stage 2

Identify partial responders

early

Switch

Stage 3

Identify ‘best’ responders later

Reduce/stop

Primary endpoint: MR3 (MMR) at 3 years

Secondary: sustained MR3

CMR on reduced dose/stop(no more bone marrows!)

EFS, PFS, OSHealth Economics, QoL

SPIRIT 3Newly diagnosed

Questions?

Thanks for listening

CMLSPIRIT 3

Steve O’BrienNorthern Institute for Cancer

Research Newcastle University Medical School

Newcastle, March 2013