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Clinical Research WALES CANCER PARTNERSHIP CONFERENCE 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 Today’s agenda 1. Dr Sahar Iqbal – Wales Cancer Research Centre Clinical Research Fellow – Neurocognitive Function after Stereotactic Radiosurgery 2. Dr Paul Shaw – Consultant Oncologist, Velindre Cancer Centre – Early phase drug-radiotherapy trials 3. Dr Rob Jones and Dr Steve Knapper – co-leads Workpackage 2 – developments in early phase trials in solid tumours and haematology WCRC Clinical Workshop Sahar Iqbal Clinical Research Fellow Brain metastases • Most common cause of intracranial malignancy • Lung, Breast, Renal, Melanoma • Treatment 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 Cerebral Blood Flow Diffusion Tensor Imaging MR Spectroscopy Neurocognitive Tests Questions? WCRC Early Phase Trials Work Package Dr Rob Jones Senior Lecturer and Consultant Medical Oncologist Cardiff University and Velindre Cancer Centre Expansion of solid tumour phase 1 trial activity WCRC Early Phase Trials Work Package • CARdiff Bcl3 inhibitor ONcology project • FAKTION CARdiff Bcl3 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 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 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 Schedule of FAKTION Treatment and Assessments ctDNA ctDNA/CT C1D1 C3D1 CT/ctDNA 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 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 Early Phase Trials for Patients with Haematological Cancers Steve Knapper Cardiff University and University Hospital of Wales AML: Many targets for therapy 1.2% NPM1+/CEBPA+ 1.2% NPM1+/CEBPA+/FLT3-ITD+ 0.2% NPM1+/CEBPA+/FLT3-TKD+ 1.0% CEBPA+/FLT3-ITD+ 0.4% CEBPA+/FLT3-ITD+/WT1+ 0.2% CEBPA+/FLT3-ITD+/FLT3-TKD+/WT1+ 7.6% NPM1+/NRAS+ 4.2% CEBPA+ 0.4% CEBPA+/WT1+/NRAS+ 0.8% NPM1+/WT1+ 2.5% CEBPA+/WT1+ 0.6% NPM1+/WT1+/NRAS+ + + 1.2% CEBPA /NRAS 15.1% NPM1+ 0.8% NPM1+/FLT3-ITD/NRAS+ 14.8% no mutation 2.1% NPM1+/FLT3-ITD/WT1+ 0.4% NPM1+/FLT3-TKD+/WT1+ 2.7% FLT3-ITD+/WT1+ 0.2% FLT3-ITD+/NRAS+ 0.6% NPM1+/FLT3-TKD/NRAS+ 0.2% NPM1+/FLT3-ITD/WT1+/NRAS+ 0.4% FLT3-ITD+/FLT3-TKD+ 0.2% NPM1+/FLT3-ITD/FLT3-TKD+/NRAS+ 6.1% FLT3-ITD+ 0.4% NPM1+/FLT3-ITD/FLT3-TKD+ 4.7% NPM1+/FLT3-TKD+ 0.4% FLT3-TKD+/WT1+ 17.4% NPM1+/FLT3-ITD 0.4% NPM1+/MLL+/FLT3-ITD 0.2% NPM1+/MLL+/FLT3-TKD+ 0.2% MLL+/FLT3-ITD/FLT3-TKD+ + 1.4% MLL /FLT3-ITD Cytogenetically normal AML (7 markers; n=485) 0.4% FLT3-TKD+/NRAS+ 0.2% WT1+/NRAS+ 1.2% WT1 + 0.6% MLL+/FLT3-TKD+/WT1+ 0.6% MLL+/FLT3-TKD+ 0.8% MLL+/NRAS+ 3.3% MLL+ 2.7% NRAS+ Döhner et al. Blood. 2010;115: 453-74. Slide courtesy of David Grimwade Mutations •TP53 •RUNX1 •DNMT3A •GATA2 (?) Relative gene expression •LEF1 •EVI1 •HBG1 •BAALC •PIM1 •ERG •MN1 Modulators of drug response •MDR status •Polymorphisms in drug metabolism/ detoxification genes •BCL2/BAX, ARC, pFOXO3A •“Stem cell phenotype” BM microenvironment •ALK5 •VEGF •CXCR4 Array profile •mRNA •miRs Impaired Host Response •CD47 Clinical Research Facility at UHW Current early phase haematology studies in Cardiff Trial Disease Funder CAMELLIA Acute myeloid leukaemia (AML) CRUK ELASTIC Myelodysplastic syndromes TAP IPI-145-06 Non-Hodgkin’s lymphoma Commercial ALP-196 Mantle cell lymphoma Commercial Decitabine + CD123 Ab Acute myeloid leukaemia Commercial MUK5 Myeloma Myeloma UK UKALL 60+ Acute lymphoblastic leukaemia (ALL) CRUK SOPRA Acute myeloid leukaemia Commercial VIOLA Acute myeloid leukaemia (relapse post transplant) TAP PHAZAR Myeloproliferative neoplasms (in transformation) TAP MONOCLE Chronic myelomonocytic leukaemia (CMML) Bloodwise TAMARIN Myeloproliferative neoplasms TAP BAY 1251152 Acute myeloid leukaemia / Myeloma Commercial Opening soon • ‘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. eat me Anti-CD47 antibodies CD47 Phagocyte cancer cell phagocytosis don’t eat me X No phagocytosis eat me phagocytosis 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 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 Monocyte-directed therapy - Tefinostat • Tefinostat is a histone deacetylase (HDAC) inhibitor that is only converted to its active form by the enzyme hCE1 in monocytoid cells Neutral, Φ-targeted esters cell cell Molecular target ester Molecular target Other cells ester hCE-1 acid Monocytes, macrophages • 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 A phase 2 study of the MONOcyte-targeted HDAC inhibitor tefinostat in Chronic Myelomonocytic LEukaemia • 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’ Thanks for your support