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Incurable blood cancer trial finds new drug better than current treatments

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials.

Patients with an incurable blood cancer – polycythaemia vera (PV) – may respond better to a new drug compared to conventional best treatment, a new clinical trial has found.

The rare cancer results in patients producing too many red blood cells and the drug, Ruxolitinib, has been found to be better at treating PV compared to the best currently available treatment. Researchers at BHP founder member the University of Birmingham – funded by Blood Cancer UK – looked at how well the drug worked in those who don’t respond well to the first line of treatment in a randomised phase-II clinical trial.

In this trial, dubbed MAJIC-PV, 39 different hospitals co-ordinated by Birmingham’s Cancer Research UK Clinical Trials Unit (CRCTU) recruited 180 people with PV. They compared ruxolitinib (a drug that targets JAK2 and is already approved for use in PV but not available in the UK) with currently available therapies. Ruxolitinib led to better control of the disease with normal blood counts and a reduced spleen size.

For the first time ever, using samples from the study, the researchers showed that both controlling the blood count and reducing mutated JAK2 by 50% led to fewer disease related events – and that those patients with reduction in JAK2 mutation lived longer, with lower risk of disease progression.

Professor Pamela Kearns, Director of the CRCTU at the University of Birmingham said: “Working on new treatments for incurable cancers is just the kind of thing that the Birmingham Cancer Research UK Clinical Trials Unit is about. I am really pleased that this important clinical trial has found that ruxolitinib has long-term clinical benefit for the ongoing treatment of patients with PV, and that further trials will be able to identify whether the drug can be used as an effective first line treatment.”

PV belongs to a group of conditions that affect the blood called myeloproliferative neoplasms (MPNs). Recently Tim Jonze from the Guardian and ex-radio one DJ David Hamilton have announced they have this form of blood cancer, raising awareness of this lesser-known disease.

The disease is caused by a mutation in a gene called JAK2 and can cause blood clots. Those living with the disease have a risk of a reduced life expectancy as well as development of more aggressive blood cancers including myelofibrosis and acute leukaemia.

One of the commonly used treatments is a drug called – hydroxycarbamide – but those whose cancer does not respond to this drug have a poor prognosis.

Professor Claire Harrison, consultant haematologist at Guy’s and St Thomas’ NHS Foundation Trust and the trial lead, said: “For some time we have wanted to be able to understand the long-term benefits of a drug such as ruxolitinib for patients with PV. This study shows several important messages about this therapy which will hopefully shortly be available for UK patients. These are that comprehensively controlling the blood count reduces disease related events, and that molecular monitoring of mutation levels may also begin to be important.

“Patient therapy is chosen on an individual basis but options have hitherto been limited for PV patients. We are now studying this drug for newly diagnosed patients in a world-first study MITHRIDATE. I would like to thank all the patients who volunteered to be part of this study, their families, UK research teams, Novartis which provided the drug and Blood Cancer UK which funded the trial infrastructure and the trial management team.

Dr Suzanne Rix, Research Funding Programme Manager at Blood Cancer UK, said: “Blood cancer is the fifth most common cause of cancer in the UK, affecting over a quarter of a million people. There is currently no cure for polycythaemia vera and there are a number of complications that can arise from it, so designing, developing and testing medicines to give patients the best outcome possible is vitally important.

“Blood Cancer UK is committed to funding excellent quality scientific research to ensure we deliver better treatments for blood cancer, faster. This trial is a great example of how collaboration between charities, academia, clinicians and pharmaceutical companies can deliver impactful results.

“Our heartfelt thanks go out to those who took part in the trial, without whom we wouldn’t have been able to collect this vital information and continue to improve the outcomes for people with blood cancer.”

Drug combination could overcome tumour resistance in paediatric cancers

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials.

Children with some solid tumours may benefit from receiving a combination of inhibitor drugs, according to interim results of research presented at the American Association of Cancer Research’s Annual Meeting 2023, held April 14-19.

The ongoing research being conducted by an international team including the University of Birmingham suggests that a combination of the PARP inhibitor olaparib (Lynparza) and the investigational ATR inhibitor ceralasertib showed clinical benefit in paediatric patients with solid tumours exhibiting DNA replication stress and/or DNA repair deficiencies.

Dr Susanne Gatz, associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham presented the study.

Dr Gatz said: “To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumour types. This is the first proof of principle that the combination is well tolerated and can lead to clinically relevant responses in paediatric cancers.”

AcSé-ESMART is an international European proof-of-concept platform trial intended to match paediatric, adolescent, and young adult patients with relapsed or treatment-refractory cancers with a treatment regimen targeted to their cancer’s mutational profile. Gatz and colleagues, including Birgit Geoerger, MD, PhD, head of the AcSé-ESMART trial, have so far evaluated 15 different treatments, mostly combination strategies, in more than 220 children following mandatory high-throughput genomic profiling of their tumours.

Arm N of AcSé-ESMART is tailored toward patients with malignancies that exhibit defects in DNA replication and damage repair. Impairments in homologous recombination (HR), a type of DNA repair, can sensitize cells to drugs called PARP inhibitors. PARP inhibitors have proven effective against specific adult cancers with HR deficiencies—most notably, mutations in BRCA1 or BRCA2. How to best use PARP inhibitors in paediatric patients where BRCA1/2 mutations are rarely found remains unclear.

Dr Gatz said: “Paediatric cancer cells proliferate rapidly and have some element of replication stress and a dependency on ATR. We think there might be a kind of primary resistance of paediatric cancers to PARP inhibitors and that combination with an ATR inhibitor could potentially overcome that.”

Gatz also explained that paediatric cancers are often driven by complex mechanisms, making it difficult to identify an effective treatment regimen. Single-agent therapies targeting one mutated protein are often insufficient in paediatric patients, necessitating additional research into combination therapies and mechanisms of response.

“So far, it is unclear if the molecular alterations based on which the patients were enrolled in this trial are the sole reasons for response,” Gatz said.

“Further, it may be difficult to identify patterns of response in specific tumour types due to the tumour-agnostic nature of the study. Nevertheless, this study design can give preliminary indications of signals in specific alterations and tumour types and can provide the basis for future clinical trials.”

Gatz and colleagues plan to evaluate biomarkers of response from the raw sequencing data of the enrolled patients, from the expression of key target proteins such as ATM, and from RNA sequencing data.

Gatz noted that these analyses may identify “molecular constellations” indicative of response to olaparib plus ceralasertib.

“There are enormously valuable drugs currently in development and, provided there is a good clinical or preclinical rationale, we need to apply them more creatively to diseases for which the drug is not currently indicated,” Gatz said.

Limitations of this study include a small, non-randomized sample intended primarily as a proof of concept and to determine the optimal dose for study expansion.

The study is as yet unpublished.

Skull model

New drug can lower brain pressure and treat blinding IIH headaches, finds trial

Written by Louise Stanley on . Posted in Clinical trials.

Patients with Idiopathic Intercranial Hypertension (IIH) – a condition which causes raised brain pressure and debilitating headaches – could be treated with an injectable peptide used for type 2 diabetes, a new trial has found.

The study, published in the journal Brain, reports on a phase two trial of a drug called exenatide, a GLP-1 receptor agonist, as a potential treatment for IIH.

The IIH Pressure Trial led by a team of neurologists from BHP founder-members the University of Birmingham and University Hospitals Birmingham found that the seven patients who received regular injections of the drug, currently approved for use in Type 2 Diabetes, experienced a drop in pressure in the brain during both short (2.5hrs and 24hrs) and long term (12 weeks) measurements.

The trial also saw significant reductions in the numbers of headaches across the 12 weeks that participants took part, with an average of 7.7 fewer days per month of headaches compared to the baseline, compared to only 1.5 fewer days in the placebo arm.

Alex Sinclair is Professor of Neurology in the Institute of Metabolism and Systems Research at the University of Birmingham, an Honorary Consultant Neurologist at University Hospitals Birmingham NHS Foundation Trust, and Principal Investigator of the study, said: “This is a major trial for the rare and debilitating condition IIH that can lead to people, usually women, going blind and suffering disabling daily headaches. There are no current licenced drugs to treat IIH and hence this result is a major step forward for IIH patients.

“We are delighted to see that the phase two trial resulted in our treatment group having lower brain pressure both immediately and after 12 weeks and nearly 8 fewer headache days across the 12-week period, and that all the women were able to continue the treatment throughout with few adverse effects. We now hope to see a much larger trial of exenatide to literally ease the pressure for the many people around the world suffering with IIH.”

Dr James Mitchell, Lecturer in Neurology at the University of Birmingham and first author of the paper said: “The results of this clinical trial are a shot in the arm for finding clinical treatments for IIH. While we need to do further trials before such a treatment could be available for patients in the future, we are encouraged by the significant results from this trial that made a real difference for those in the treatment arm and this treatment may prove relevant for other conditions resulting in raised brain pressure.”

In this study the drug was given as a twice daily injection into the subcutaneous tissue. To reduce the need for frequent injection in the future, a once-weekly subcutaneous injection called Presendin will be trialled though University of Birmingham Start-up company, Invex Therapeutics.

Shelly Williamson, the Chair of patient charity IIH UK said: “This is such exciting progress. New drug options is vitally important for IIH and this trial brings hope to the millions of patients living with the condition. We very much look forward to the next steps and seeing the drug tested in two large Phase 3 clinical trials.”

The IIH Advance is a Phase 3 clinical trial in Adolescents run in the UK, sponsored by the University of Birmingham and IIH Evolve is running in adults internationally sponsored by Invex Therapeutics. Ultimately the aim is to gain enough evidence to allow the drug to be licensed for use in IIH patients in the future.

Funding boost for Birmingham rare disease research

Written by Louise Stanley on . Posted in Birmingham Health Partners, Clinical trials, Early diagnosis and detection, Experimental medicine.

BHP founder-member the University of Birmingham has been awarded a £500k Pathfinder Award from the medical research charity LifeArc which will support early-stage projects with a focus on translational development in rare diseases.

The successful projects have now been announced following an internal selection process. Research, conducted by the University of Birmingham and working across Birmingham Health Partners, will begin this spring.

Professor Timothy Barrett, Director of the Centre for Rare Disease Studies (CRDS) Birmingham, commented: “I am thrilled that our Centre for Rare Disease Studies at the University of Birmingham has been successful in securing a LifeArc Pathfinder Award. We are working closely with other organisations from Birmingham Health Partners; Birmingham Children’s and Women’s Hospital and University Hospitals Birmingham; to fund a number of impactful translational research projects through the fund. Our uniquely diverse patient population, and strength in partnership ensures that we are in the best possible position to drive forward research in rare diseases to accelerate progress and ultimately improve patients’ lives.”

Around the world, approximately 300 million people are living with a rare disease. A disease is considered rare if it affects less than 1 in 2000 people. Around 80% of rare diseases have a genetic component. They are often chronic, progressive, degenerative and frequently life-threatening with no existing cure.

Owing to the nature of rare disease, small patient populations make research challenging. Lack of scientific knowledge and quality of information on rare diseases can mean that misdiagnosis is common and treatment options may be limited.

The Centre for Rare Disease Studies supports basic and applied research, in order to build a pipeline of translational research from gene discovery to improving the diagnosis, clinical management and treatment of these disorders.

Research projects that will benefit from the Pathfinder Award include:

      • The NEEDED Study (NanoporE Enhances Diagnosis in rarE Disease), led by Dr Hannah Titheradge, which will investigate the effectiveness of a new type of genome sequencing to identify rare diseases.
      • A proof-of concept study, led by Dr Nekisa Zakeri, which aims to develop a novel ‘off-the-shelf’ T cell immunotherapy capable of providing more effective treatment for patients with a rare liver cancer.
      • The CATCH Study (CArbalivefor the Treatment of CHoleastic Disease), led by Dr Palak Trivedi, looks into whether a new medical device can absorb toxins from the gut to reduce inflammation and scarring in primary sclerosing cholangitis; a rare progressive liver disorder for which no medical treatment has been shown to slow disease progression.
      • Dr Richard Tuxworth and Professor Zubair Ahmed, whose research in DNA damage in nerve cells has already resulted in patent applications covering pathways and mechanisms that could provide new therapies for neurological conditions and spinal cord injury, will now work with Professor Andrew Beggs and Dr Chiara Bardella to investigate the potential for one of these pathways (the ATM-Chk-2 pathway) as a basis for therapies to tackle rare neurological conditions that appear early in childhood.
      • Dr Sovan Sarkar’s study aims to improve the health of patients with rare childhood-onset forms of neurodegeneration by correcting the process of autophagy that normally removes undesirable cellular materials which is detrimental to brain cells called neurons.

Dr Hannah Titheradge, a Consultant in Clinical Genetics at Birmingham Women’s and Children’s NHS Foundation Trust, will investigate the effectiveness of nanopore sequencing – a new type of real time genome sequencing – on a larger group of patients. Previously tested on a very small sample, this new technology showed promise for improving our capability to diagnose rare diseases.

Nanopore sequencing reads more letters in an individual’s genome than the standard sequencing method used to diagnose rare genetic disorders. The NEEDED Study (NanoporE Enhances Diagnosis in rarE Disease) will explore a more detailed approach that could improve the percentage of patients who receive an important genetic diagnosis, which can help those patients and their families face their challenges feeling better informed.

Dr Hannah Titheradge commented: “Receiving a diagnosis can be an uphill challenge for patients with rare diseases and their families. These individuals often wait years for a final diagnosis, having undergone multiple tests and procedures. Having a diagnosis is very important because it helps these individuals better understand their health problems and plan for the future. Some genetic conditions are treatable, and a diagnosis is the first step towards accessing these treatments. We can also understand whether any other family members’ health may be affected. For these reasons, any advance that can be made in improving rare disease diagnostics is invaluable.”

Samira Fakire, Business Manager at LifeArc, added: “We hope that the Pathfinder Award will encourage more researchers to move into the rare disease space and promote the development of a translational culture – pushing more discoveries from the lab into meaningful real-world benefits for patients.”

Leukaemia trial tests Covid vaccine strategies to combat immune suppression

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials.

Patients with the most common form of leukaemia – Chronic Lymphocytic Leukaemia (CLL) – are being invited to take part in a trial that could help them build Covid-19 antibodies following vaccination, when they previously have had poor responses.

Blood cancer patients are known to be at high risk of Covid-19 and many are part of the ‘forgotten 500k’ who are not well protected by Covid-19 vaccination and are therefore still very cautious going about their daily lives in contrast to those who are not immunocompromised.

Research has found that CLL patients who take either ibrutinib or acalabrutinib over the long term are not responding to Covid vaccination as well as those who are not taking the drug. Their antibody response is usually much lower, meaning the vaccine is not as effective in protecting against the disease.

Dr Helen Parry, Associate Professor at the Institute of Immunology and Immunotherapy at the University of Birmingham, is leading the IMPROVE trial and explained: “This study aims to determine if it is possible to improve the immune response by pausing ibrutinib or acalabrutinib treatment for a short period around the time of vaccination. It will also monitor whether pausing this treatment is well tolerated by patients by looking for symptom flare.

“At present there is no advice for CLL patients regarding whether pausing their treatment is the safest approach to vaccination, but anyone who participates in the trial will help to build a vital evidence base so that appropriate advice can be given in future.”

Patients interested in participating must be able to travel to one of the six trial sites: Birmingham, Stoke on Trent, London, Dudley, Oxford or Nottingham.

Anyone interested in taking part in the trial can email the trial team or call 0808 175 1455, and further information is available on the IMPROVE trial website.

New heart attack drug trialled in Birmingham

Written by Louise Stanley on . Posted in Clinical trials.

A new partnership between BHP clinical-academic institutions and Acticor Biotech will see patients with heart attacks treated with glenzocimab, a promising new class of drug, for the first time.

The drug – which has potential to improve the long-term outcomes for heart attack patients – will be trialled in two UK acute care hospitals: the Queen Elizabeth Hospital, Birmingham and the Northern General Hospital, Sheffield.The trial will be run at the University of Birmingham with expert clinicians from the Institute of Cardiovascular Sciences and University Hospitals Birmingham NHS Foundation Trust, bringing together clinical trials expertise from two founding members of BHP.

The randomised, double-blind Phase 2b LIBERATE study will recruit more than 200 patients to test the tolerance and the efficacy of glenzocimab 1000 mg, versus placebo, to reduce heart damage following a myocardial infarction (MI), commonly known as a heart attack. Bringing together experience in running multi-site trials from the Clinical Trials Units and expertise in heart diseases, the team will see whether glenzocimab will reduce the amount of dead heart tissue in patients following an ST-segment elevation myocardial infarction (STEMI), the most serious type of heart attack.

Professor Jon Townend, Consultant Cardiologist at University Hospitals Birmingham, Honorary Professor of Cardiology in the Institute of Cardiovascular Sciences at the University of Birmingham, and Chief Investigator of the trial said: “We look forward to starting this exciting trial of a new drug for heart attacks which are still only too common.

“Although immediate opening of the blocked coronary artery by angioplasty in cases of heart attack is now routine, significant heart damage still occurs. Glenzocimab reduces clot formation and laboratory findings have been impressive.

“There are strong reasons to believe that this new drug may improve outcomes and this randomised blinded trial is the right way to test this theory.”

Dr Mark Thomas, Associate Professor of Cardiology at the University of Birmingham and Honorary Consultant Cardiologist, who designed the trial and led its development, said: “This trial will help us establish whether glenzocimab is a safe and effective drug for preventing the kind of clotting that can lead to serious damage to the heart following a heart attack.

“We’re delighted to work with Acticor Biotech to see whether this new class of drug has the potential to improve the outcomes of our patients with heart attacks. While the immediate care provided for a heart attack is effective for improving patient survival, there is more we can do to prevent long-term damage to the heart.”

Gilles Avenard, Chief Executive Officer and founder of Acticor Biotech said: “Glenzocimab has already delivered very promising results in the treatment of acute ischemic stroke and we hope to confirm its therapeutics potential in another severe indication.

“We are proud of this Phase 2b study launch, which allows glenzocimab development programme extension to myocardial infarction. We would like to congratulate all the teams involved, the University of Birmingham particularly, sponsor of this study.”

Glenzocimab, a humanized monoclonal antibody (mAb) fragment directed against the platelet Glycoprotein VI (GPVI), was developed by Acticor Biotech for the treatment of cardiovascular emergencies, including stroke.

This new drug, currently being trialled for strokes, stops the functioning of platelets that cause abnormal clotting of blood. While platelet function is normally important to stop bleeding, this drug specifically targets only dangerous clotting inside damaged blood vessels called thrombosis that can cause strokes and heart attacks.