CML
SPIRIT 3
Steve O’Brien
Northern Institute for Cancer Research
Newcastle University Medical School
Newcastle, March 2013
Thank you!
Imatinib
vs
Dasatinib
www.spirit-cml.org
Acknowledgements
SPIRIT 1 study design
Arm A: Imatinib 400
Chronic phase CML
Within 3 months of
diagnosis
R
Arm B: Imatinib 800
Arm C: Imatinib 400 + IFN
• Randomised open label study
3 treatment arms
• Arm A: 400mg daily imatinib
• Arm B: 800mg daily imatinib
• Arm C: 400mg daily imatinib plus 180mg weekly PEGinterferon a
Primary endpoint
To compare overall survival in the three arms at 5 years
N=259
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
P
(P ajusted on Sokal
score )
Imatinib
400 mg
(N = 159)
Imatinib
600 mg
(N = 160)
Imatinib
+
Cytarabine
(N = 158)
Imatinib
+ Peg-IFN
(N = 159)
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)
9 (5-14)
8 (4-13)
8 (4-13 )
16 (12-24 )
0,0132 (0,0134)
REPONSE %
(CI 95 %)
At 24 months
Undetectable
transcript
Preudhomme al., New England Journal of Medicine, 2010
SPIRIT 2: Study Design
Arm A
Imatinib 400
Chronic phase CML
within 3 months of diagnosis
R
Arm B
Dasatinib 100
Randomised open label study
Primary endpoint: 5 year EFS
Secondary: cyto, molec response, tox
810 of 810 patients recruited!
246 since last year
172 sites currently participating
136 sites have recruited
41 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
Side effects
QoL
Efficacy
Greatest
benefit
(cost)
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
Stage 2
Stage 3
Compare first
line intervention
Identify partial
responders
early
Identify ‘best’
responders later
Randomised
Switch
Reduce/stop
SPIRIT 3
Newly diagnosed
Primary endpoint: MR3 (MMR) at 3 years
Secondary: sustained MR3
CMR on reduced dose/stop
(no more bone marrows!)
EFS, PFS, OS
Health Economics, QoL
Imatinib
Stage 1
Compare first
line intervention
Randomised
R
Nilotinib
1000 patients
Stage 1: up front randomisation
Overall Survival (OS)
BCR-ABL (IS) at 3 months ≤1% vs. 1-10% vs. >10%
≤1%
1-10%
>10%
BCR-ABL (IS)
n
5Y-OS
≤1%
218
97%
1-10%
283
94%
>10%
191
87%
Hanfstein et al.
Leukemia. 2012 Mar 26. doi: 10.1038/leu.2012.85. [Epub ahead of print]
p-value
n.s.
0.012
Stage 2
Identify partial
responders
early
Switch
Imatinib >10% PCR
~25% patients
Stay in SPIRIT 3
Switch to ponatinib
Nilotinib >10% PCR
~10% patients
Stage 2: nilotinib/ponatinib?
for >10% @ 3 months
Comparison
Nilotinib
Nilotinib
Ponatinib
Ponatinib
Imatinib
Imatinib
A
B
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?
(DESTINY pilot)
Stage 3
Minimum of 3 years:
Halve dose if MMR for 1 year
Identify ‘best’
responders later
Minimum of 4 years:
Stop if remain in MMR
Reduce/stop
How much is
Primary endpoint: MR3 (MMR) at 3 years
Secondary: sustained MR3
CMR on reduced dose/stop
(no bone marrows)
EFS, PFS, OS
enough?
Health Economics, QoL
Stage 1
Stage 2
Stage 3
Compare first
line intervention
Identify partial
responders
early
Identify ‘best’
responders later
Randomised
Switch
Reduce/stop
SPIRIT 3
2013
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
Stage 2
Stage 3
Compare first
line intervention
Identify partial
responders
early
Identify ‘best’
responders later
Randomised
Switch
Reduce/stop
SPIRIT 3
Newly diagnosed
Primary endpoint: MR3 (MMR) at 3 years
Secondary: sustained MR3
CMR on reduced dose/stop
(no more bone marrows!)
EFS, PFS, OS
Health Economics, QoL
Thanks for
listening
Questions?
CML
SPIRIT 3
Steve O’Brien
Northern Institute for Cancer Research
Newcastle University Medical School
Newcastle, March 2013