cml spirit 3 steve o’brien northern institute for cancer research newcastle university medical...
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CMLSPIRIT 3
Steve O’BrienNorthern Institute for Cancer
Research Newcastle University Medical School
Newcastle, March 2013
• 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.
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
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
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
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