CML Research for better treatment Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School CML patient meeting, 11 th October 2014

Clinical trials Phase I studies designed to find out the most effective dose of the drug and the possible side effects of the drug. Phase II studies carried out on different cancers so that the research team can find out how active a particular drug is. Only about 20 to 30 patients with each cancer. Phase III studies to compare a new treatment with the best treatment currently available. Phase III trials are usually randomised and may include a double blind procedure. Others include – Sample banking; Epidemiological and phase IV long term safety monitoring usually post approval

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CML trials in the UK Destiny low level disease (MMR) reduce then stop if possible pilot study CHOICES SPIRIT trials

Around the world Germany – nilotinib France – interferon alpha US – dasatinib, early response India – efficacy of generics

Thank you…

Acknowledgements Data analysis and presentationStephen O’Brien, Corinne Hedgley, Sarah Adams, Paul Terril, John McCullough Trial management and data collection, Newcastle Corinne Hedgley, Lynn Seeley, Caroline Hodgson, Ruth Bescoby, Carrie Page, Angela Fallows, Laura Brown, Gemma Gills, Wendy Banks, Meg Buckley, Leanne Woolmer, Wendy Osborne PCR & DNA/RNA biobankingLetizia Foroni, Gareth Gerrard, Hammersmith Cell biobankingTessa Holyoake, Alan Hair, Glasgow Study Management CommitteeSO’B, CH, Richard Clark, Liverpool; Jane Apperley, Hammersmith, Mhairi Copeland (Chair of CML WG) Data Monitoring CommitteeJohn Goldman, Keith Wheatley, Graham Dark, Charles Schiffer SponsorNewcastle Hospitals NHS Foundation Trust FunderBristol Myers Squibb: Glenn Kroog, Milayna Subar, Sonal Chavda-Sitaram Chief InvestigatorStephen O’Brien Sitesn=172. Thanks to all our investigators and site staff. Patientsn=814. A huge thank you to all participating patients. NCRI CML Working GroupDragana Milojkovic, Jenny Byrne, Hugues de Lavallade, Adam Mead, Graeme Smith, Brian Huntley, Richard Szydlo, Andy Goringe, Naumann Butt, Sameer Tulpule, Shamyla Siddique, Bernie Ramsahoye, Mhairi Copland (Chair)

814 patients recruited Recruitment closed Feb hospitals set up 145 recruited patients

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 Primary endpoint: 5 year EFS Secondary: cytogenetic, PCR response, toxicity n=814 N=407

SPIRIT 2 summary Largest investigator-conducted randomised trial of dasatinib vs imatinib n=814 median follow up 3 years Both drugs generally well tolerated 523 of 812 (64.4%) continue on study medication Imatinib: GI tox; Dasatinib: pleural effusions, headaches No difference in cardiovascular events MR 3 rate at one year is: imatinib 43%, dasatinib 58% 783/812 (96.4%) remain alive overall No difference in progression or overall survival

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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 p-value ≤1% 1-10% >10% Hanfstein et al. Leukemia Mar 26. doi: /leu

riskbenefit

R R Imatinib Nilotinib Group I Group N Imatinib Ponatinib Nilotinib Stage 1 Randomise (500 to each group) Stage 2 Selective switch (3 months or later) Stage 3 Reduce dose, stop (after minimum 3 years) Primary endpoint MR3 at 3 years Imatinib Ponatinib Nilotinib Aim to reduce and stop (if MR3 for at least 1 year) Aim to reduce and stop (if MR3 for at least 1 year) n=500

CML Research for better treatment Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School CML patient meeting, 11 th October 2014

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