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CML SPIRIT 1, 2 (and 3…) Prof Stephen O’Brien Northern Institute for Cancer Research, Newcastle University Medical School.

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Presentation on theme: "CML SPIRIT 1, 2 (and 3…) Prof Stephen O’Brien Northern Institute for Cancer Research, Newcastle University Medical School."— Presentation transcript:

1 CML SPIRIT 1, 2 (and 3…) Prof Stephen O’Brien Northern Institute for Cancer Research, Newcastle University Medical School

2 Acknowledgements All patients involved in the SPIRIT trials All who put patients in the studies Study Management Committee – Richard Clark, Jane Apperley, Corinne Hedgley, Steve O’Brien Data Monitoring Committee – John Goldman, Keith Wheatley, Graham Dark Trial team, Sponsor – Corinne Hedgley, Caroline Hodgson, Lynn Seeley, Kerry Oliver, Wendy Banks, Meg Buckley, Amanda Tortice, Richard Carr, Gary Ford PCR & analysis – Letizia Foroni (n=3,800!), David Marin, Richard Szydlo SPIRIT 2 team at BMS

3 Dates for your diary CML patient meeting – Glasgow – Mhairi Copeland – Sat 17 th November 2012 CML, MPD professional meeting – Newcastle?? – Friday 1 st February 2013?

4 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

5 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  Primary endpoint To compare overall survival in the three arms at 5 years N=259 SPIRIT 1 study design Chronic phase CML Within 3 months of diagnosis Arm A: Imatinib 400 Arm B: Imatinib 800 Arm C: Imatinib 400 + IFN R

6 SPIRIT 1 Presentation/publication No ‘per-arm’ publication to date – DMC advice Survival endpoint awaited Other studies reviving IFN… – TOPS, Gimmema, German, French Submission to ASH 2013?

7 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) 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) 16 (12-24 ) 0,0132 (0,0134)

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9 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

10 www.spirit-cml.org Imatinib vs Dasatinib Thank you!

11 SPIRIT 2: Study Design Chronic phase CML within 3 months of diagnosis Chronic phase CML within 3 months of diagnosis Arm A Imatinib 400 Arm A Imatinib 400 Arm B Dasatinib 100 Arm B Dasatinib 100 Randomised open label study Primary endpoint: 5 year EFS Secondary: cyto, molec response, tox

12 NCRN-adopted study. 810 patients Newcastle Hospitals Sponsor, BMS fund/supply drug 1:1 randomised, open label Newly-diagnosed CML (within 3 months) 2 treatment arms (405 patients on each) – Arm A: 400mg daily imatinib – Arm B: 100mg daily dasatinib Dasatinib supply, cost saving (approx £14M to date) Primary end point event-free survival at 5 years Secondary endpoints include cytogenetic & PCR responses, time to treatment failure

13 670 of 810 patients recruited 246 since last year 209 in previous year 165 sites currently participating 136 sites have recruited 41 more than last year

14 SPIRIT 2 – recruitment update (May 2012)  670 patients recruited average 4-5 patients each week at current rate of recruitment anticipate last patient will be recruited early 2013  165 sites open for recruitment 136 sites have recruited at least one patient top recruiter (Liverpool) has recruited 43 patients an average site has between 4 and 5 patients

15 SPIRIT 2 – safety update (May 2012) 204 SAEs received to date Regular review of potential signals – progressions, deaths and cancers – pleural effusions (inc. chest drains) – pulmonary arterial hypertension (shortness of breath, particularly where this unexplained) – SAEs attributable to non-neutropenic infection DMC review – Confirmed study should continue

16 SPIRIT 2 – PAH update (May 2012) Small number across all studies Diagnosis difficult Mild breathlessness, no pleural effusion, right heart cath Incidence estimated to be about 0.4% Mechanism not known Appears to be reversible Other TKIs used to treat PAH Protocol amendment (including revised PIS) in progress with outline of clinical guidance for approach to this – Clinical guidance will NOT recommend automatic right heart cath Risk of PAH (probably reversible) vs effective CML treatment

17 SPIRIT 2 publications Predictive value of early molecular response in patients with chronic myeloid leukaemia treated with first line dasatinib. Marin et al. ASH 2011 & Blood 2012 Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia. Rezvani et al. Blood 2012 Biobank

18 Cumulative incidence of CCyR Cumulative incidence of MMR Time from start of therapy (months) p<0.001 BCR-ABL/ABL >10%, n=11 BCR-ABL/ABL <10%, n=117 CCyRMMR BCR-ABL transcript levels at 3 months predicts 2 year cumulative incidence of CCyR and MMR

19 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

20 NICE TA251: first line treatment – 25 April 2012 – Imatinib & nilotinib approved – Subject to Patient Access Scheme (PAS) – Dasatinib not approved (no PAS offered) TA 241: second line – 13 January 2012 – Same as above

21 NICE Dasatinib – “People currently receiving dasatinib that is not recommended according to 1.3 should be able to continue treatment until they and their clinician consider it appropriate to stop” – Minimum free supply in SPIRIT 2 to 2018

22 Imatinib Dasatinib Nilotinib Bosutinib Ponatinib 2000201020152005 Development License NICE approved Off patent ?? TKIs in CML

23 So why continue SPIRIT 2? PCR response rates are higher with nilotinib (ENESTnd) and dasatinib (Dasision study) No significant difference in survival at three years Imatinib will be off patent in 2015/16 (cost effectiveness) Patients who fail imatinib or dasatinib in SPIRIT 2 can get nilotinib Long term follow up and identification of longer term side effects Continued cost savings to NHS all dasatinib patients receive free drug until at least 2018 Approx. £49M Timing: SPIRIT 2  SPIRIT 3 UK can lead

24 Other first-line trials HD imatinib – Not convincing Nilotinib and dasatinib – Look good at 2/3 years (ASCO updates) – No evidence of survival benefit Imatinib (& other TKIs) plus IFN – Ditto – All the rage in Europe… Bosutinib, ponatinib

25 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

26 ENESTnd study. Kantarjian et al. Lancet Oncology 2011: 12: 841

27 ‘Isotypes’ of Otto Neurath and Gerd Arntz Thanks to David Spiegelhalter

28 ENEST nd Progression to AP/BC at 24 months Kantarjian et al. Lancet Oncology 2011: 12: 841 Imatinib 400 1 n=283: 12 events (4.2%)Nilotinib 300 2 n=282: 2 events (0.7%)

29 ENEST nd All deaths at 24 months Kantarjian et al. Lancet Oncology 2011: 12: 841 Imatinib 400 1 n=283: 11 events (3.8%)Nilotinib 300 2 n=282: 9 events (3.2%)

30 Current state of play Most CML patients are fine – There are more and more of them… Not much difference between TKIs? – Apart from cost… – Use wisely/selectively We really need to figure out how to reduce and/or stop treatment for a lot more patients

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32 Projected prevalence of CML £290M per year £464M per year £???? Huang et al. Cancer 2011: doi: 10.1002/cncr.26679 USA: 311, 591,917 UK: 62,218,761 USA: 311, 591,917 UK: 62,218,761

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34 NHS spending on CML In next 10 years… Between £290M - £460M per annum Over next ten years… £2-3 billion?

35 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

36 Stage 1 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no more bone marrows!) EFS, PFS, OS Health Economics, QoL SPIRIT 3

37 Stage 1 Compare first line intervention Randomised Stage 1: up front randomisation Nilotinib R R Imatinib 1000 patients

38 BCR-ABL (IS) n 5Y-OS ≤1% 21897% 1-10% 28394% >10% 19187% 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]

39 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 3 Switch drug Stay in SPIRIT 3 Switch drug

40 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: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no bone marrows) EFS, PFS, OS Health Economics, QoL

41 Stage 1 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no more bone marrows!) EFS, PFS, OS Health Economics, QoL SPIRIT 3

42 SPIRIT 3 timelines CTAAC application submitted July meeting Sponsorship agreed Funding: pharma Regulatory approvals Q4 2012, Q1 2013 SPIRIT 2 recruitment complete: Q1 2013 SPIRIT 3 first patient: June 2013

43 CML first-line: where are we up to? SPIRIT 1 SPIRIT 2 What’s going on with NICE? – Implications for trials Prevalence of CML, pressing questions SPIRIT 3

44 CML s.g.o’brien@ncl.ac.uk Slides available at: www.spirit-cml.org Prof Stephen O’Brien Northern Institute for Cancer Research, Newcastle University Medical School


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