MONOCLE study in CMML
Chronic myelomonocytic leukaemia (CMML) is an uncommon form of cancer that causes a buildup of cells called monocytes in the bone marrow and blood. It mainly affects older people and the average length of survival is only 18 months. There are currently very few treatment options for CMML and there is a pressing need for new drug treatments which can target the abnormal monocytes without causing unacceptable side effects.
Tefinostat is a new drug, taken by mouth, which only becomes active after it is inside monocytes. In lab studies, performed in the Cardiff ECMC, tefinostat was effective against monocyte tumours, including CMML and some types of AML.
The MONOCLE study is a ‘phase 2’ trial, funded by Bloodwise and sponsored by Cardiff University, which will allow us to test the effectiveness of tefinostat, as well as monitoring for side effects, in 40 patients with CMML at 12-15 hospitals in the UK. Blood and bone marrow samples from MONOCLE patients will be tested in the Cardiff laboratory to help us better understand how tefinostat works and to identify which patients are most likely to benefit in future. MONOCLE will open in 2016.
Enquiries about MONOCLE may be addressed to Dr Steve Knapper.
FIESTA is a Phase Ib and pharmacokinetic trial of AZD4547 in combination with gemcitabine and cisplatin, initiated through the ECMC/Astra Zeneca Combinations Alliance with John Chester as CI. Gemcitabine plus cisplatin is a standard-of-care, combination chemotherapy regimen for patients with bladder cancer, in both neoadjuvant and palliative settings. AZD4547 is a selective fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with potential to improve outcomes for tumors with FGFR mutation and/or over-expression, as commonly seen in bladder cancers.
This study has so far demonstrated that it is feasible to combine AZD4547 with full doses of Gemcitabine and Cisplatin, without excessive toxicity. The result of the dose escalation phase 1 component of this study has been submitted as an abstract to this year's ASCO meeting. Comparison of toxicities of Gemcitabine and Cisplatin with and without AZD4547 is under way in a randomised expansion cohort foradvanced bladder cancer patients.
Faktion is a Phase 1b/2 study, examining whether inhibition of AKT with AZD 5363 can improve breast cancer outcomes when combined with fulvestrant, a hormone therapy. This study is run through Wales Cancer Trials Unit, sponsored by Velindre NHS Trust, and has Co-CI’s Dr Robert Jones from Cardiff with Dr Sacha Howell from Manchester.
Cardiff ECMC Senior Executive Group members were involved in the conception of this protocol, and also the delivery of the trial to breast patients in the region, out of the Clinical Trials Research Unit, based at Velindre Cancer Centre. The Phase 1 part of this study has now been completed, having opened in May 2014, and has now moved into Phase 2, opening throughout the UK.
To date, 10 patients have been recruited to the trial and are supported by our team of highly skilled Research Nurses, one of which is ECMC funded. Recently, a Clinical Research Fellow MD has also been appointed to analyse translational samples, including circulating tumour DNA, to investigate bio-markers that may determine treatment efficacy. It is hoped that high levels of patients locally and nationally continue to participate in trial activity.
Breast cancer patients often have the oestrogen receptor protein in their tumours and so can benefit from anti-hormonal drugs. However, a significant number of these patients develop resistance to their anti-hormonal treatment and relapse, which can mean a poorer prognosis. Cardiff ECMC supports expertise in staining clinical breast cancer samples (including those taken at relapse) and anti-cancer agent screening using anti-hormone-resistant cell models. The research aims to provide new drug targets for clinical trials that could benefit
anti-hormone-resistant breast cancer patients.
For example, the research has demonstrated that drugs inhibiting activity of a receptor tyrosine kinase protein called Ret are effective in blocking growth and aggressiveness of anti‑hormone resistant cell models in the laboratory. Ret signalling activity can also be detected within breast cancer samples from patients who become resistant to anti‑hormones. These findings have helped provide pre-clinical rationale underpinning the concept that Ret targeting alongside anti-hormonal treatment might have potential to control resistance. This is being explored through the ongoing UK Phase II breast cancer trial FURVA, which is being lead from Wales.
Cardiff’s ECMC scientists are part of a UK team to develop a simple blood test capable of detecting levels of leukaemia cells remaining after intensive chemotherapy. Working alongside experts from King’s College London, a team from Cardiff University’s School of Medicine led by Dr Robert Hills provided the crucial data from current patients with leukaemia.
The test helps predict which patients with acute myeloid leukaemia (AML) are at risk of their cancer returning in the future, helping to guide doctors on what further treatment is needed.
The data collected from patients has given a new insight into Acute Myeloid Leukaemia (AML). Looking at the disease while people are receiving treatment has given a unique opportunity to learn much more about how best to treat. What they have been able to identify is a group of patients who otherwise would be thought to do quite well, who in fact have a very poor prognosis, and who are not well served currently. This opens up the exciting prospect that we can do the same for other groups of patient as well.
The patients all had AML driven by faults in the NPM1 gene – which is the most common genetic sub-type of the disease and accounts for a third of all cases. The ECMC funded the initial mutation screening to identify patients who are NPM1 mutant.
Development of NGS analysis for solid tumours
The ECMC post-holder is based in the all Wales Genetic Laboratory and works closely with the NHS Genetic diagnostic team to support clinical trials, local researchers, and the rapid translation of research findings into clinical practice. To date, this post has enabled NGS panel design and sequence analysis from FFPE incorporating the requirement for highly fragmented and minimal amounts of DNA. Analysis is now focussed on the challenging detection of SNVs and small ins/dels. Bioinformatic pipelines have been developed through close collaboration with the Wales Gene Park. Pipelines have been successfully delivered for the analysis of the gene panels developed.
The post-holder has supported the FOCUS4, CR-UK SMP clinical trials, the local molecular characterisation of biobanked samples, and the Genomics England QA. They also have a role in training and education for these technologies.
The Cancer Research UK Cardiff Cancer Research Centre has expanded organoid-based studies by funding an additional position as part of its tumour stratification programme. Dr. A. Hollins was appointed to that position in October 2014 and Dr K. Ewan succeeded him in the ECMC position. Dr Ewan will continue this research using Ser Cymru funding until the end of September 2015.
The Pre New Agents Committee (Pre NAC) is a pool of expertise available to the South Wales cancer research community on the 'bench-to-bedside' therapeutic pipeline. Its purpose is to increase the rate of translation of new therapeutic approaches (either with new treatments, new combinations or repurposed treatments) from the lab to phase I trials. It is accessible to all who hope to see their work go forward into a new clinical approach.
Those who are working up an application to submit to a funding committee are particularly encouraged to take advantage of the committee. The Pre NAC aims to provide a friendly review prior to formal submission.
Applicants will be asked to fill in a form online which will be reviewed.
Applicants to the Pre NAC will then be matched with relevant expertise on the panel, who can provide informal mentorship until the project is ready to be presented.
The Pre NAC will also circulate opportunities for funding, often overlooked, e.g. from drug companies.
The committee will meet 3-4 times per year, in cycle with the NAC meetings.
To register your project with the Pre NAC, please complete the application form here.