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Clinical Research

Clinical Research. W A L E S C A N C E R P A R T N E R S H I P C O N F E R E N C E. What’s special about ‘clinical’ research. Patients Clinical research is based on patients agreeing to enter research or trials

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Clinical Research

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  1. Clinical Research W A L E S C A N C E R P A R T N E R S H I P C O N F E R E N C E

  2. What’s special about ‘clinical’ research • Patients • Clinical research is based on patients agreeing to enter research or trials • Hope that the patients themselves will derive benefit, but the likelihood of this varies considerably between studies • They may be exposed to more risks or side effects than standard of care • They usually end up spending more time within the healthcare sector and this may have financial implications • The people most likely to benefit are other (future) patients • For many years the most effective clinical research is done via collaborations • Clinicians and scientists • Clinicians from different specialities • Multiple clinicians across different centres or countries • Clinicians and patients

  3. Today’s agenda • Dr Sahar Iqbal – Wales Cancer Research Centre Clinical Research Fellow – Neurocognitive Function after Stereotactic Radiosurgery • Dr Paul Shaw – Consultant Oncologist, Velindre Cancer Centre – Early phase drug-radiotherapy trials • Dr Rob Jones and Dr Steve Knapper – co-leads Workpackage 2 – developments in early phase trials in solid tumours and haematology

  4. WCRC Clinical Workshop Sahar Iqbal Clinical Research Fellow

  5. Brain metastases • Most common cause of intracranial malignancy • Lung, Breast, Renal, Melanoma • Treatment

  6. Neurocognition and Radiotherapy • Rates are high with WBRT • 52 - 91% reported in studies (Chang et al., 2009; Brown et al., 2016) • Lower rates with SRS • 24 - 63.5% (Chang et al., 2009; Brown et al., 2016) • Structures Involved? • Hippocampus • Amygdala • Entorhinal Cortex • Limbic Lobe • Fornix • Pre-frontal Cortex

  7. Cerebral Blood Flow

  8. Diffusion Tensor Imaging

  9. MR Spectroscopy

  10. Neurocognitive Tests

  11. Questions?

  12. WCRC Early Phase Trials Work PackageDr Rob Jones Senior Lecturer and Consultant Medical Oncologist Cardiff University and Velindre Cancer Centre

  13. Expansion of solid tumour phase 1 trial activity

  14. WCRC Early Phase Trials Work Package • CARdiffBcl3 inhibitor ONcology project • FAKTION

  15. CARdiffBcl3 inhibitor ONcology project • Preclinical work from Richard Clarkson lab identified Bcl3 as important determinant in metastatic spread in breast cancer • Andrea Brancale and Andy Westwell groups designed and synthesised Bcl3 inhibitor that inhibits metastatic spread and acts as a cytostatic in animal TNBC models • Compound currently in clinical development undergoing full toxicity assessment. WCRC funded Luke Piggott is project manager • We plan to open First in Class Phase 1 trial in Cardiff Q3/4 next year

  16. FAKTION Background • All ER+ve metastatic breast cancers will develop resistance to endocrine therapy • Most common endocrine therapy in post-menopausal women are Aromatase Inhibitors (AI’s) • Activation of PIK3CA pathway associated with resistance to endocrine therapy • Akt is a downstream target of PIK3CA • Fulvestrant(Selective Estrogen Receptor Degrader, SERD) is approved for use in patients who have progressed on AI’s

  17. Cell free tumour DNA (ctDNA) Liquid Biopsy • Tumour DNA that has been shed into the bloodstream • By apoptosis, necrosis or secretion • Small (ave. 160-180bp), unstable DNA fragments, associated with proteins • Short half life Diaz and Bardelli, 2014 Journal of Clincial Oncology 32

  18. Schedule of FAKTION Treatment and Assessments ctDNActDNA/CTCT/ctDNA C1D1 C3D1 Progression Diagnostic paraffin tissue block, blood from entry, 8 weeks, and progression for PIK3CA, AKT and other biomarker, analysis. Each treatment cycle is 28 days

  19. Cell free tumour DNA (ctDNA) Liquid Biopsy • Compare mutational status of key genes from archival specimen (first diagnosis), trial baseline (resistance to AI), on treatment, progression (resistance to therapy) • Correlation of mutations with treatment outcomes may define biomarkers which determine success or failure of treatment. • Refine which patient groups should be given therapy • Provides new targets to drug to help improve treatments in resistant groups

  20. Early Phase Trials for Patients with Haematological CancersSteve Knapper Cardiff University and University Hospital of Wales

  21. AML: Many targets for therapy • Mutations • TP53 • RUNX1 • DNMT3A • GATA2 (?) • Relative gene expression • EVI1 • BAALC • ERG • MN1 • LEF1 • HBG1 • PIM1 • Modulators of drug response • MDR status • Polymorphisms in drug • metabolism/ detoxification genes • BCL2/BAX, ARC, pFOXO3A • “Stem cell phenotype” • BM microenvironment • VEGF • CXCR4 • ALK5 • Array profile • mRNA • miRs Slide courtesy of David Grimwade • Impaired Host Response • CD47

  22. Clinical Research Facility at UHW

  23. Current early phase haematology studies in Cardiff

  24. ‘Phagocytosis’ is the name of the process by which cells are ‘eaten’ by the immune system • AML cells avoid phagocytosis by expressing CD47 that delivers a “don’t-eat me” signal. • Anti-CD47 antibodies block the “don’t eat me” signal allowing phagocytosis of cancer cells. Anti-CD47 antibodies CD47 eat me don’t eat me eat me X Phagocyte cancer cell phagocytosis phagocytosis No phagocytosis

  25. Phase I dose escalation trial of the Humanized Anti-CD47 Monoclonal Antibody Hu5F9-G4 in Acute Myeloid Leukaemia • ‘3+3’ design – 5 planned dose cohorts (up to 30 patients) • For patients with Relapsed or ‘Refractory’ AML • Patients treated in Cardiff, Manchester (Christie), Oxford

  26. Chronic Myelomonocytic Leukaemia (CMML) • Rare cancer of ‘monocytoid’ cells in the bone marrow and blood • Generally elderly patients • Wide range of features including anaemia, disabling symptoms and transformation to AML • Very limited current treatments and very few clinical trials

  27. Monocyte-directed therapy - Tefinostat • Tefinostatis a histone deacetylase (HDAC) inhibitor that is only converted to its active form by the enzyme hCE-1 in monocytoid cells • Pre-clinical work by Jo Zabkiewicz and Marie Gilmour confirmed selective activity of tefinostat against monocytic tumours such as CMML or monocytoid AMLs • European phase 1 study established safety in patients with haematological malignancies • MONOCLE will assess the safety and clinical efficacy of tefinostat in CMML Neutral, Φ-targeted esters cell cell Molecular target ester Molecular target ester acid hCE-1 Monocytes, macrophages Other cells

  28. A phase 2 study of the MONOcyte-targeted HDAC inhibitor tefinostatin Chronic MyelomonocyticLEukaemia • About to open at 17 hospital sites around the UK • 40 CMML patients will each be treated with tefinostat for 24 weeks • Clinical efficacy and safety will be assessed • Translational lab studies to assess: hCE-1 expression differential acetylation changes targeted gene sequencing ‘acetylomics’

  29. Thanks for your support

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