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Cannabinoid-based drug trial for brain tumours launches in Birmingham

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

A major UK clinical trial of an oral spray containing cannabinoids to treat recurrent glioblastoma has opened in the UK. Funded by The Brain Tumour Charity and coordinated by the Cancer Research UK Clinical Trials Unit at BHP founder-member the University of Birmingham, the three-year phase II trial  will investigate whether combining nabiximols and chemotherapy can help extend the lives of people diagnosed with recurrent glioblastoma.

Anyone interested in this study, which is called ARISTOCRAT, should speak to their medical team first to ensure they are eligible to participate.

It will recruit more than 230 glioblastoma patients at 14 NHS hospitals across England, Scotland and Wales in 2023 including Birmingham, Bristol, Cambridge, Cardiff, Edinburgh, Glasgow, London, Liverpool (Wirral), Manchester, Nottingham, Oxford and Southampton.

Professor Pamela Kearns, Director of the Cancer Research UK Clinical Trials Unit (CRCTU) at the University of Birmingham, which is co-ordinating the trial, said:

“ARISTOCRAT represents a significant step in our journey towards finding safe and effective treatments for the most aggressive brain tumours. By testing innovative combinations of drugs we hope to improve the outcome for this challenging disease.

“We’re immensely proud to be able to bring this trial to patients with the support of the Brain Tumour Charity and thanks to the generosity of all those who gave to the crowdfunding campaign.”

Glioblastoma is the most aggressive form of brain cancer with an average survival of less than 10 months after recurrence.

In 2021, a phase I clinical trial in 27 patients found that nabiximols could be tolerated by patients in combination with chemotherapy, and has the potential to extend the lives of those with recurrent glioblastoma.

Should the trial prove successful, experts hope that nabiximols could represent a new, promising addition to NHS treatment for glioblastoma patients since temozolomide chemotherapy in 2007.

In August 2021, a fundraising appeal by The Brain Tumour Charity, backed by Olympic champion Tom Daley, raised the £450,000 needed for this phase II trial in just three months, and Jazz Pharmaceuticals has generously agreed to provide nabiximols and matched placebo free-of-charge to patients on the ARISTOCRAT trial.

Participants will self-administer nabiximols or a placebo spray and will undergo regular follow-ups with the clinical trial team, including blood tests and MRI scans. This will also be one of the first trials to integrate with The Brain Tumour Charity’s app BRIAN.

Principal Investigator, Professor Susan Short, Professor of Clinical Oncology and Neuro-Oncology at the University of Leeds, said:

“We are very excited to open this trial here in Leeds and very much look forward to running the study which will tell us whether cannabinoid- based drugs could help treat the most aggressive form of brain tumour.

“The treatment of glioblastomas is extremely challenging. Even with surgery, radiotherapy and chemotherapy, nearly all of these brain tumours re-grow within a year, and unfortunately there are very few options for patients once this occurs.

“Cannabinoid-based drugs have well-described effects in the brain and there has been a lot of interest in their use across different cancers for a long time now. Glioblastomas have receptors to cannabinoids on their cell surface, and laboratory studies on glioblastoma cells have shown these drugs may slow tumour growth and work particularly well when used with temozolomide.

“We now have the opportunity to take these laboratory results, and those from the phase I trial and investigate whether this drug could help glioblastoma patients live longer in this first-of-a-kind randomised clinical trial.”

How can I take part in the trial?

Your treating oncologist will be aware of the study if it is open in your hospital or can refer you to a treating centre if necessary. Please speak to your treatment team about eligibility for the trial.

For more information visit the ARISTOCRAT web page on the Cancer Research UK Clinical Trials Unit website. 

UHB launches mRNA cancer vaccine trial for colorectal cancer

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

BHP founder-members University Hospitals Birmingham NHS Foundation Trust (UHB) has become the UK’s first site to launch the BioNTech Messenger RNA (mRNA) cancer vaccines trial which aims to recruit 10,000 people across the UK.

Launching within the NIHR Clinical Research Facility (CRF) at Queen Elizabeth Hospital Birmingham, mRNA vaccines are one of the most exciting experimental developments to emerge from the COVID-19 pandemic – with strong indications that they could become powerful anti-cancer treatments.

Traditionally, vaccines use dead or weakened viruses to stimulate the immune system into recognising or creating harmless antibodies, so when exposed to the real virus, the body is better placed to fend off an overwhelming infection. mRNA is a genetic material that copies instructions found in DNA, using them to make proteins that carry out functions in the body.

Efficiency and speed are part of the appeal of mRNA vaccines. The manufacture of traditional inactivated virus vaccines takes months as scientists are required to grow these on a huge scale, inactivate the virus, and then formulate it to administer in the general population. mRNA vaccine manufacture only requires the right sequence of genetic instructions.

At UHB, this mRNA trial aims to recruit patients with high-risk stage II and stage III colorectal cancers where there is no standard of care treatment to offer the patient following surgery. Each mRNA vaccine delivered will be personalised to the individual patient.

Around 42,900 people are diagnosed with colorectal cancers in the UK each year. It is the 4th most common cancer in the UK. In Birmingham and Solihull alone, almost 700 people are diagnosed with a colorectal cancer each year.

Dr Victoria Kunene, Consultant Oncologist and Principal Investigator for the trial at UHB, said: “I am really very excited that we have been able to lead the way in setting up this arm of the trial, and am looking forward to being part of the wider vaccine program at UHB.

“We are proud to have an impressive team aptly capable of safely delivering these studies here in the West Midlands, and it is a real pleasure to be part of this transformational trial.”

Prof Simon Ball, Chief Medical Officer, said: “A diagnosis of cancer is devastating for patients and their families; this trial represents a monumental step forward in providing not just hope, but a real promise of delivering better outcomes for patients with colorectal cancer, for whom there is not always a standard of care treatment available following surgery.

“Our research teams, supported by the NIHR, have a proven, distinguished track record in delivering vital trials that make significant contributions to medical and scientific discovery with the patient at the very heart; we’re immensely proud to be able to play a strong part in this here in the West Midlands.”

Participants randomised to receive the study treatment will receive 15 treatments of over one year, followed up for at least 36 months. The treatment is, in essence, a personalised medicine for post-operative patients with high-risk stage II/III colorectal cancer, for whom there is no standard of care treatment and involves the development and testing of an individualised cancer treatment called RO7198457.

UHB is the first site open for this trial – a multi-site, open-label, Phase II, randomized, controlled trial to compare the efficacy of RO7198457, versus watchful waiting in resected, Stage II (high risk) and Stage III colorectal cancer patients who are ctDNA positive following resection.

‘Individualised’ means that the treatment is made individually for each participant according to their unique cancer. This is then tested for mutations which create a unique fingerprint. The goal of an individualised cancer treatment approach is to help train the immune system to recognise and attack cancer cells.

Participants who are randomised to the observation group will be followed up for at least 48 months and visit the research site every three months. Care is provided to ensure safety during trial participation, including an informed consenting process, regular follow up where biomarkers and all reported outcomes are collected and analysed.

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.”