PMAL Consortium and Associated Trials 2016 CONFIDENTIAL The new name for Leukaemia amp Lymphoma Research Tackling Diffuse Large Bcell Lymphoma 2 Clinical Problem Standard of care RCHOP results in cure rates around 75 ID: 1033700
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1. Precision Medicine For Aggressive Lymphoma (PMAL) Consortium and Associated Trials2016CONFIDENTIALThe new name for Leukaemia & Lymphoma Research
2. Tackling Diffuse Large B-cell Lymphoma2Clinical ProblemStandard of care, RCHOP, results in cure rates around 75%Relapsed/ refractory patients have largely ineffective treatment options with very poor outcomes, around 21% 3 year EFS.Heterogeneous DiseaseTranslocations- Myc 10%, Bcl2 20%, Bcl6 30%>200 mutations with low frequency- few >10%, 30-50 mutations in each lymphoma.Cell of Origin by GEP- ABC, GCB, PMBL and unspecified. Lymphoma biology guides potential therapeutic targets.Novel agentsVariety of novel agents in development targeting a range of mechanisms including immunotherapy and small molecules. Several new agents show revolutionary effects in other malignancies (eg melanoma) and other B-cell disorders. To date this has not been translated to DLBCL.
3. University of SouthamptonClinical Trials UnitPeter Johnson, Andrew Davies, Gareth Griffiths, Tom Cummin, Shamim Kazmi-Stokes (HB - Bath)LeedsHMDS laboratoryBioinformatics hubAndrew Jack, Reuben Tooze, Cathy Burton, David Westhead, Matt Care, Sharon Barrans, Michael Bentley University of OxfordMolecular haematologyBioinformaticsAnna Schuh, Simon HolmesSt Bartholomew’s, LondonGenomics, cfDNAJude Fitzgibbon, Shamzah ArafUniversity of Cambridge Molecular pathologyGenomicsMing DuPMAL - A national network of diagnostic and therapeutic researchSAB - Jonathan Pearce - Lymphoma AssociationAdrian Newland - Chair, Scientific Advisory BoardJohn Radford – NCRI Clinical Studies Group Chair
4. Consortium work streams – developing molecular assays, longitudinal analysis and clinical trials4PMAL Consortium
5. Illumina, Affymetrix, 14M genomicsPMAL Process Map5WS1 - Development and validation of robust predictive molecular assays for use in stratification WS3 - Bioinformatics and statisticsWS2 - Developing assays for longitudinal analysis and clonal evolutionWS4 - Prospective testing of stratified therapy with novel agentsPharmaceutical collaboratorsPt. biopsies and plasma samples from 4 sources 9 milestones5 milestones7 milestones13 milestonesBloodwise & Scientific Advisory Board
6. Studies to Date and in Development- Southampton Clinical Trials Unit6REMoDl-B – Largest Phase III RCT in DLBCL. Utilising prospective molecular testing to investigate RCHOP + bortezomib. Completed recruitment ahead of schedule >1000 patients- awaiting primary endpoints.PMAL ConsortiumMaPLe – Nationwide molecular study of DLBCL- recruited > 1000 patients- study recently expanded to include 3000 participants. Mutations & cell of origin. Identify targetable mutations for/at relapse.Phase 1b/II – 3x DLBCL novel agent clinical trials in development- first on schedule to open Summer 2016, the second 1 January 2017. Multi-arm Multi-stage/ Umbrella study in R/R DLBCL– In development and discussions with pharmaceutical collaborators to include novel agents and novel combinations in a multi-arm multi-stage molecularly stratified clinical trial for relapsed/refractory DLBCL. Academic Sponsor with provision to provide data as supportive evidence for FDA licensing.
7. Multi-Arm Multi-Stage/ Umbrella trial7Future of Clinical TrialsAdaptive MAMS clinical trials provide the next generation of contemporary trial designs allowing assessment of multiple agents targeting molecular subgroups. The traditional trial designs are likely ill-equipped to answer the research questions posed to improve DLBCL therapy. Biomarker-driven interim analysis allows responses to be assessed promptly. Seamless phase progression allows fast-tracking of promising agents to provide evidence for clinical use. Prospective molecular testing and analysis allows subgroups to be identified and further investigated.
8. MAMS/ umbrella trial- simplified schema 8Relapsed/ Refractory DLBCL- Central Screening- Single Master ProtocolMolecular profile/ mutation status to direct Agents- (MaPLe, baseline biopsy)Biomarker-drivenInterim AnalysisLack of response- end unsuccessful armsExpand arms with interim success to meet clinical endpoints- PFS/ OSSeamless phase progressionTo include mCR determined by PET and exploratory biomarkers- (cfDNA)Adaptive trial design- arms/ agents/ targeted mutations and seamless transition between phasesProspective mutation analysis and COO with outcomesArm AArm DArm CArm BArm ECross-over between arms at progression