World-first trial tests cannabis-based drug on aggressive brain tumours
A major UK trial of cannabis-based drug Sativex in treating the most aggressive form of brain tumour is to launch at 15 NHS hospitals, following promising results from a phase I study in 27 patients.
The new phase II trial, led by the University of Leeds, will assess whether adding Sativex – an oral spray containing cannabinoids THC and CBD – to chemotherapy, could extend life for thousands diagnosed with a recurrent glioblastoma. Currently, it has an average survival of less than 10 months.
The drug, already used in treating multiple sclerosis, was found to be tolerable in combination with chemotherapy, with the potential to extend survival, in a phase I trial in glioblastomas earlier this year.
While the phase I study observed that more patients were alive after one year in the Sativex arm compared to the placebo arm, the study was not sufficiently powered to show survival impact.
The new three-year phase II trial (ARISTOCRAT), funded by The Brain Tumour Charity and co-ordinated by the Cancer Research UK Clinical Trials Unit at the University of Birmingham, is due to begin recruiting more than 230 patients across all UK nations in early 2022, subject to sufficient funds being raised.
Having seen its income drop by more than 25% last year due to the pandemic and forced to pause its regular research grant funding programme, The Brain Tumour Charity has today launched an appeal to raise the £450,000 needed to open the trial as soon as possible.
Experts hope that, should the trial prove successful, Sativex could represent one of the first additions to NHS treatment for glioblastoma patients since temozolomide chemotherapy in 2007.
Professor Susan Short (pictured above), is the principal investigator on the new trial and Professor of Clinical Oncology and Neuro-Oncology at Leeds. She said: “The treatment of glioblastomas remains 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.
“Glioblastoma brain tumours have been shown to have receptors to cannabinoids on their cell surfaces, and laboratory studies on glioblastoma cells have shown these drugs may slow tumour growth and work particularly well when used with temozolomide.
“Having recently shown that a specific cannabinoid combination given by oral spray could be safely added to temozolomide chemotherapy, we’re really excited to build on these findings to assess whether this drug could help glioblastoma patients live longer in a major randomised trial.”
Tackling aggressive brain cancer
Glioblastomas are the most common and most aggressive form of brain cancer, with around 2,200 people diagnosed each year in England alone. They are usually fast-growing and diffuse, with poorly-defined boundaries and thread-like tendrils that extend into other parts of the brain.
Almost all glioblastomas recur even after intensive treatment including surgery, radiotherapy and chemotherapy, and average survival is just 12-18 months from first diagnosis.
Over the last decade there has been significant global interest within both patient and scientific communities about the activity of cannabinoids in brain tumours, with the view that cannabinoid-based products may not only help relieve symptoms but could also have a positive impact on survival.
Several pre-clinical laboratory studies have suggested that cannabinoids THC and CBD may reduce brain tumour cell growth and could disrupt the blood supply to tumours – but to date, clinical evidence that they could treat brain tumours has been limited.
In this new phase II trial, researchers will assess whether adding Sativex to the current standard chemotherapy treatment (temozolomide) could offer extra time to live for adults diagnosed with a recurrence of their glioblastoma after initial treatment.
‘Life beyond a glioblastoma diagnosis’
Stephen Lee, 62 from Leyland in Lancashire, took part in the phase I trial of Sativex in 2015 after his glioblastoma returned following initial treatment. Stephen was first diagnosed in 2010, just a few months after he had very sadly lost his older brother to the same disease. Stephen said: “My diagnosis was very sudden and was one of those days you never forget. Having had to leave work early with a severe headache and a stabbing pain in my right eye, my wife insisted that we go straight to hospital after what my brother had experienced.
“I was admitted that same day, had a scan and that’s when they identified it was a brain tumour. I had the operation the following week, and beforehand my wife and I agreed that we wanted to stay positive, to keep living our lives and to enjoy however much time we had together.
Pictured: Stephen Lee with his wife
“I joined the early trial of Sativex in the hope that it could improve my quality of life, but I also thought it was important to do so as the chemotherapy and radiotherapy I was having had all been trialled by other people before it could be used safely. I thought it only right and proper that I followed in their footsteps and joined a trial to help prove a new drug which could benefit so many people in the future with a recurring glioblastoma.
“I took the oral spray 10 times a day, and it was easy as I could take it wherever we were going, even while out for dinner. While I don’t know whether I had Sativex or the placebo, since the trial finished in 2016, all my MRI scans have been clear.
"This new trial is so important as it will give people hope that there could be life beyond a glioblastoma diagnosis and that there are other treatments being trialled to support them to live their lives.”
The ARISTOCRAT trial plans to recruit 232 participants across a minimum of 15 hospitals: two thirds of the participants will be given temozolomide plus Sativex, while one third will be given temozolomide plus placebo.
Sativex, manufactured by GW Pharma, is an oromucosal spray containing 1:1 THC (Delta-9-tetrahydrocannabinol) and CBD (cannabidiol), with the active ingredients being absorbed in the lining of the mouth, either under the tongue or inside the cheek.
Participants will be asked to administer up to 12 sprays per day (or to the maximum dose they can tolerate if fewer than 12) of Sativex or placebo oral sprays.
Participants will then undergo regular follow-up including clinical assessment (every four weeks), blood tests, MRI scans (every eight weeks), and they will complete quality of life questionnaires. This will also be one of the first trials to integrate with The Brain Tumour Charity’s app BRIAN.
The trial will measure whether adding Sativex to chemotherapy extends the overall length of patients’ lives (overall survival), delays the progression of their disease (progression-free survival) or improves quality of life.
In the initial phase I study, the most common side-effects reported were fatigue, headache, vomiting and nausea, which were mostly classed as being mild-moderate in severity.
Dr David Jenkinson, Interim CEO at The Brain Tumour Charity, which is funding the trial, said: “We hope this trial could pave the way for a long-awaited new lifeline that could help offer glioblastoma patients precious extra months to live and make memories with their loved ones.
“With so few treatments available and average survival still so heartbreakingly short, thousands affected by a glioblastoma in the UK each year are in urgent need of new options and new hope.
“We know there is significant interest among our community about the potential activity of cannabinoids in treating glioblastomas, and we’re really excited that this world-first trial here in the UK could help accelerate these answers. The recent early-stage findings were really promising and we now look forward to understanding whether adding Sativex to chemotherapy could help offer life-extension and improved quality of life, which would be a major step forward in our ability to treat this devastating disease.
“But we also know that for many, this trial won’t come soon enough. In the meantime, while other cannabis-based products may help alleviate symptoms, there is insufficient evidence to recommend their use to help treat brain tumours. For anyone considering using cannabis-based products or other complementary therapies, it’s vital that you discuss these with your medical team first, as they could interact with other treatments such as anti-epileptic medicines or steroids.
Cannabis Oil Use: Growing Phenom Appears Safe, Helpful in Brain Cancer
After tracking the progress of about 20 patients with brain cancer who used cannabis, a neuro-oncologist found that the substance caused them no harm, had few side effects and did not interfere with conventional treatments.
Since some of his patients with brain cancer were likely to use cannabis anyway, Nicholas A. Blondin, M.D., figured he might as well oversee that part of their care. After tracking the progress of about 20 of these patients, he found that the supplement caused no harm in this population, had few side effects and did not interfere with conventional treatments.
While Blondin has not yet been able to draw conclusions about whether cannabis has extended overall survival in the patients, he did hear from some that it has improved their quality of life.
Director of neuro-oncology services at Associated Neurologists of Southern Connecticut, in Fairfield, and medical director of the St. Vincent’s Brain Tumor Center, in Bridgeport, the doctor reported his methods and observations in a poster presented Nov. 17 at the 22 nd Annual Meeting and Education Day of the Society for Neuro-Oncology, in San Francisco.
“The patients mostly feel pretty good,” he said. “It does not make them any worse. Besides fatigue if they take too much, which quickly reverses, there are no side effects. It’s not common amongst neuro-oncologists now, but it’s part of the routine care I provide in my practice.”
Blondin shared his results because cannabis use among brain cancer patients is a scarcely studied but growing phenomenon, with one Facebook group about cannabis oil treatment for people who have glioblastoma boasting 9,000 members. Since cannabis isn’t FDA-approved or regulated and there’s little or no instruction about its use in medical schools, “neuro-oncologists need to know about it and understand the treatment potential, pitfalls and side effects,” he said. “Talk about it with your patients, because patients are doing it.”
Medical marijuana is legal in Connecticut and in the majority of American states, and Blondin works with a state-run dispensary to get prescriptions for his patients.
“I mention the option to patients to use with standard treatment when diagnosed, and see if they’re interested, or if their families want them to try it,” he said. He advises against cannabis if the patient has a history of addiction or psychiatric or cognitive disabilities, but considers most he treats to be eligible.
When patients are interested, Blondin registers them with the state, which allows them to buy cannabis at Connecticut dispensaries.
“They grow it all, and manufacture the cannabis oil, in Connecticut, and the quality control is good,” he said. “I know how many milligrams patients are taking. I’ve developed a relationship with the pharmacist at one dispensary, and they know what I want to do. We’re all learning together.”
Working Through Challenges
One challenge is that no particular dose has been established as effective for patients with brain cancer, Blondin said.
Patients who take the drug palliatively are typically looking to ease symptoms ¾ including headaches, nausea, vomiting, gastrointestinal issues, anxiety, lack of appetite and insomnia. These patients usually find it most effective to smoke cannabis oil, often using vaporizer pens, Blondin said. Others use cannabis oil in the hopes that it will kill cancer cells, because there is some evidence in mouse models that cannabinoids, taken in combination with the standard treatment Temodar (temozolomide), can increase the effectiveness of the chemotherapy, he said. The oil comes in foil packets with syringes that are used to inject the substance into capsules, which are then swallowed. Another alternative is a sublingual spray.
In studies, mice were given 10 mg/kg of the oil, so that’s the highest dose Blondin recommends. He suggests that, if patients are experiencing fatigue, they are taking too much. The best way for these patients to find their ideal dose, he said, is to cut back on the amount of oil they’re taking and increase it every two days until they begin to experience fatigue.
Another complicating factor is that it isn’t entirely clear which ingredients in cannabis might be helpful for patients with brain cancer: THC, CBD or a combination, Blondin said.
Patients who take THC experience a high, which may be acceptable for those looking to ease insomnia or anxiety, he said. On the other hand, he said, CBD, which is non-psychoactive, also seems to work well for anxiety. In addition to consulting with Blondin, patients can choose their treatments and doses by doing research online or on social media, seeking advice from the pharmacist at a local dispensary or checking with a private consulting firm such as Green Health Consultants, the doctor said.
A final additional challenge is that cannabis represents an out-of-pocket cost for patients, Blondin said.
His study tracked three groups of patients: low users, who basically registered for cannabis at the behest of their caregivers, but then never tried it; palliative users; and therapeutic users.
Tracked were five astrocytoma patients, four of whom used palliatively and one therapeutically; three anaplastic astrocytoma patients, one of whom used palliatively and two therapeutically; and 12 glioblastoma patients, including three low-use patients, two who used palliatively and seven who used therapeutically. Some started earlier in the course of their treatment than others. Blondin authorized the first of his patients to use medical marijuana on March 3, 2014, and that was when he initiated his effort to track outcomes. In all, he approved four patients to use cannabis in 2014, six in 2015, four in 2016 and six so far this year. His data cutoff date for the study presented at SNO was June 12, 2017.
All of his patients who are taking cannabis palliatively have reported that it is effective, Blondin said. Among those using cannabis therapeutically, he said, all seven glioblastoma patients were alive at data cutoff; their cannabis use had ranged from two to 30 months.
Blondin intends to keep studying the issue and hopes that cannabis will be investigated in clinical trials as a therapy for this population. He is considering crowdsourcing with patients, especially long-term survivors of brain cancer who use cannabis, to learn more about the doses and methods of delivery they choose for themselves, and what they have found effective. “I would want to have other doctors who are interested pool their data,” he added, “so we can find out what’s going on.”