Transcript Clinical research - Wales Cancer Partnership

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
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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?
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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+
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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
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‘Phagocytosis’ is the name of the process by which cells are ‘eaten’ by the immune system
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AML cells avoid phagocytosis by expressing CD47 that delivers a “don’t-eat me” signal.
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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