A clinical trial adding Sativex (a cannabis-based medicine) to standard treatment, temozolomide, to find out if it is beneficial for patients whose glioblastoma brain tumour has returned after treatment
| ISRCTN | ISRCTN11460478 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11460478 |
| EudraCT/CTIS number | 2021-005214-34 |
| IRAS number | 1004427 |
| ClinicalTrials.gov number | NCT05629702 |
| Secondary identifying numbers | RG_21-001, IRAS 1004427, CPMS 52902 |
- Submission date
- 20/09/2022
- Registration date
- 25/10/2022
- Last edited
- 16/08/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
Background and study aims
Glioblastoma multiforme (GBM) is a type of brain tumour. When it is first diagnosed, patients are usually treated with surgery and then a combination of radiotherapy and chemotherapy with temozolomide. Unfortunately, although this often slows or stops the disease from growing for a period of time, in most cases, usually a few months after the end of the original treatment, the tumour starts to grow again. This can be detected by a magnetic resonance imaging (MRI) scan (a type of imaging that visualises the internal structures). When this happens patients may experience new symptoms or a repeat of previous symptoms.
There are few treatments available that work well at this stage to slow the growth of the tumour. Therefore, we need to develop new and better treatments to make patients live longer and feel better. The ARISTOCRAT trial is investigating whether adding a second drug (Sativex, a cannabinoid or cannabis-based medicine) to the drug already used, temozolomide, works better than temozolomide alone. Temozolomide is the chemotherapy drug that patients will have had before, both with radiotherapy and then afterwards by itself.
In a small trial already completed investigating the combination of temozolomide and Sativex, there were some interesting results suggesting that taking both drugs together was safe to give and may have an effect on the growth of brain tumours. To see if this treatment does work we need to do a much larger trial and compare the new treatment (temozolomide plus Sativex) to temozolomide (temozolomide plus placebo).
Who can participate?
Patients aged 16 years old and over with recurrent GBM
What does the study involve?
The study will find out whether the addition of Sativex to standard temozolomide treatment improves how long patients live, delays the growth of their tumours and/or improves their quality of life.
What are the possible benefits and risks of participating?
We cannot promise that you will benefit directly from participating in this trial. It is possible that the treatment you receive will be more effective or have different side effects. However, we will not know this until the results of the trial are available. All the information that we get from this trial will help improve the treatment of patients with recurrent glioblastoma in the future.
There is a risk that there is no clinical benefit to a patient receiving trial treatment. However, there is also the possibility that the results may be positive and that the treatment may cause tumour shrinkage and/or prolong survival. Patients will be made fully aware of this both verbally, and in written communication within the Patient Information Sheet (PIS).
Patients in this trial will be at risk of side effects or toxicity of temozolomide, Sativex and potential unknown risks due to the combination of the two drugs. These drugs have been used in combination in a Phase I study and no significant concerns were raised. The toxicity profile of both drugs in monotherapy is well-known and documented. Any adverse events experienced by the patients will be reviewed at each clinic visit. Patients are also advised in the PIS to notify their trial doctor or research nurse immediately if they experience any of the side effects listed in the PIS. Adverse Events that are related to the Investigational Medicinal Products and Serious Adverse Events will be recorded and reported to the ARISTOCRAT Trial Office.
During the trial, patients will have routine blood samples taken during the trial to assess ongoing safety. The risks of having blood taken from a vein include pain, bruising or infection at the site where the blood was taken, and fainting. Blood samples will be grouped as much as possible to minimise the number of times blood is taken to reduce risk to patients.
Effects on operating machinery: There is a risk that temozolomide and Sativex may affect patients’ ability to use machines safely. This is because the drugs may cause them to feel tired or dizzy, which may impair their judgement and performance of skilled tasks. Patients should not operate machinery or tools if they have side effects such as tiredness, sleepiness or dizziness. Furthermore, patients with recurrent GBM are not permitted to drive. Patients will be made fully aware of this in written communication within the PIS.
There is a risk that if a patient (or their partner) becomes pregnant while receiving trial treatment or immediately after, the unborn baby could be affected. For this reason, sites will ensure that all females of childbearing potential undergo a pregnancy test prior to receiving trial medications. All patients with childbearing potential will be educated regarding the need for adequate contraception whilst they are receiving trial drugs and for at least 6 months afterwards. Should a patient become pregnant whilst receiving trial treatment, treatment will be stopped and the pregnancy outcome will be monitored. If a patient's partner becomes pregnant during this period, we would also like to collect details of the outcome of the pregnancy with their permission.
All staff involved in the trial are fully aware of the importance of confidentiality and the Caldicott principles. Patient confidentiality will be maintained at all times during participation in the trial and once the patient has completed the trial. Under no circumstances will any patient identifiers be published. Patients are made aware of the patient information sheet and asked to consent to the personal identifiers that may be used on trial documentation and trial samples. The trial will be conducted in accordance with the UK Policy Framework for Health and Social Care Research, the applicable UK Statutory Instruments, (which include the General Data Protection Regulation (GDPR) (Regulation (EU) 2016/679 and the Data Protection Act 2018) and GCP.
Sativex/placebo will be shipped to sites unblinded. Blinding will be performed by local pharmacies, who could reveal treatment allocation to patients, the clinical team or CRCTU staff. Unblinding must be approved by a consultant-level clinician. Results of urine testing for other cannabinoid use are for research purposes only, but could unblind the trial data so will not be provided to the patient, clinical team or trials office, except to one delegated staff member not working on the trial. Cannabinoids are not routinely tested except for legal reasons; GPs will be advised not to share the presence of cannabinoids if it shows in a patient’s blood or urine.
Patients will complete additional Health-Related Quality of Life (HRQoL) questionnaires. There is a risk that the patient may be unable to complete the HRQoL questionnaires or become upset when completing them. Prior to completing each HRQoL questionnaire, a member of the Site Research Team should discuss the questionnaires with the patient and answer any questions they may have. If a participant requires assistance from a caregiver or member of the Site Research Team, this should be recorded on the HRQoL Booklet.
Urine testing for cannabinoid use is above the standard of care. Urine tests will be performed by the patient during their clinic visit, with support from site staff if necessary. A urine test is considered a safe and non-invasive form of testing and there is no risk associated with these tests.
Where is the study run from?
Cancer Research UK Clinical Trials Unit, University of Birmingham (UK)
When is the study starting and how long is it expected to run for?
August 2022 to February 2026
Who is funding the study?
The Brain Tumour Charity (UK)
Who is the main contact?
Mr Rhys Mant, aristocrat@trials.bham.ac.uk
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-sativex-for-people-with-glioblastoma-aristocrat
Contact information
Scientific
Leeds Institute of Medical Research
St James’s University Hospital
Leeds
LS9 7TF
United Kingdom
 ORCID ID |
0000-0003-4423-7256 |
|---|---|
| Phone | +44(0)113 343 8434 |
| S.C.Short@leeds.ac.uk |
Principal Investigator
Leeds Institute of Medical Research
St James’s University Hospital
Leeds
LS9 7TF
United Kingdom
| Phone | +44(0)113 343 8434 |
|---|---|
| S.C.Short@leeds.ac.uk |
Public
ARISTOCRAT Trial Office
Cancer Research UK Clinical Trials Unit
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 414 6788 |
|---|---|
| aristocrat@trials.bham.ac.uk |
Study information
| Study design | Randomized placebo-controlled double-blind parallel-group study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | No participant information sheet available |
| Scientific title | A randomised controlled phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma |
| Study acronym | ARISTOCRAT |
| Study hypothesis | To establish whether the addition of cannabinoids (Sativex) to standard temozolomide (TMZ) treatment improves overall survival time (OS) in MGMT methylated recurrent glioblastoma multiforme compared to the addition of placebo to TMZ. To establish the impact of adding cannabinoids to TMZ in terms of progression-free survival time (PFS), health-related quality of life (HRQoL) and adverse events in this setting. |
| Ethics approval(s) | Approved 19/10/2022, London - Westminster REC (Health Research Authority, Equinox House, City Link, Nottingham Centre, NG2 4LA, UK; +44 (0)207 104 8066; westminster.rec@hra.nhs.uk), ref: 22/LO/0630 |
| Condition | Glioblastoma multiforme |
| Intervention | All patients in Arm 1 and Arm 2 will receive standard temozolomide (TMZ). This is 150mg/m2 for cycle 1, increasing to 200mg/m2 for subsequent cycles, once daily for days 1-5 orally at the start of each 28-day cycle, up to a maximum of 6 cycles. In addition to standard TMZ, patients will receive Sativex or Sativex-matched placebo, up to 12 sprays per day up to a maximum of 6 cycles, self-titrated over days 1-14 in cycle 1. Patients will be randomised to trial medication in a double-blinded manner using a computer minimisation technique developed by CRCTU. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Sativex (cannabinoids), temozolomide |
| Primary outcome measure | Overall survival time (OS), defined as the time in whole days from the date of randomisation to the date of death from any cause, measured using patient survival until the date of death. Patients who are alive at the time of analysis will be censored at the date last seen alive. |
| Secondary outcome measures | 1. Overall survival measured using patient survival at 12 months (and 6 and 24 months) 2. Progression-free survival time, defined as the time in whole days from the date of randomisation to the date of the first documented evidence of disease progression or death (from any cause), measured using Response Assessment for Neuro-Oncology (RANO) criteria at screening, weeks 10, 22, 30 then 3 monthly (as per standard of care) for up to a minimum of 52 weeks from the start of trial treatment 3. Health-related quality of life measured using the EORTC QLQ-C30, EORTC BN20, single items from the EORTC item library, and the EQ-5D-5L at screening and then every 8 weeks until the end of treatment 4. Adverse events measured using CTCAE v5.0 at 4-weekly intervals post-start of treatment up to progression or withdrawal |
| Overall study start date | 09/08/2022 |
| Overall study end date | 01/02/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | 234 |
| Participant inclusion criteria | Current inclusion criteria as of 31/08/2023: 1. Histological diagnosis of MGMT promoter methylated, IDH wild type (WT) glioblastoma multiforme (GBM) with consistent local molecular pathology (repeat biopsy at recurrence is NOT required) 2. First recurrence of GBM planned for systemic treatment as determined by local Multidisciplinary Team (MDT), including agreement of a Consultant Neuro-Radiologist that imaging changes are most in keeping with recurrence and not pseudo-progression and patient is planned for systemic treatment. Patients with a prior recurrence treated by surgical resection alone are eligible at time of first recurrence planned for systemic treatment. 3. Patients must have received initial first-line treatment with standard dose conventionally fractionated radiotherapy (i.e., 40 Gy in 15 fractions or 54-60 Gy in 28-33 fractions; other regimes may be considered in consultation with the ARISTOCRAT Trial Office) with concomitant and adjuvant temozolomide (TMZ) 3.1 Minimum of 3 cycles of adjuvant TMZ must have been received 3.2. Minimum of SD (or PR/CR) at the end of first-line treatment 4. ≥3 months since day 28 of the last cycle of TMZ 5. Karnofsky Performance Status ≥60 6. Adequate hematologic, renal, and hepatic function within 14 days prior to randomisation: 6.1. Absolute neutrophil count (ANC) ≥1.5 x 109/L 6.2. Platelet count ≥100 x 109/L 6.3. Serum creatinine clearance (measured or calculated (using local standard practice)) >30 ml/min 6.4. Total serum bilirubin ≤1.5 x upper limit of normal (ULN) 6.5. Liver transaminases <2.5 x ULN 7. If surgery has been performed for first recurrence then the wound must be adequately healed and there must be residual enhancing disease on MRI within 21 days of surgery or new enhancement at later follow-up deemed suitable for systemic treatment 8. Recovered from previous treatment side-effects ≤ Grade 2 9. If on systemic steroids, must be on stable (≥7 days) or decreasing dose of steroids 10. Willing and able to provide trial-specific informed consent 11. Willing and able to comply with trial requirements 12. Aged 16 years old and over 13. Able to start treatment within 28 days of randomisation Previous inclusion criteria: 1. Histological diagnosis of MGMT promoter methylated, IDH wild type (WT) glioblastoma multiforme (GBM) with consistent local molecular pathology (repeat biopsy at recurrence is NOT required) 2. First recurrence of GBM planned for systemic treatment as determined by local Multidisciplinary Team (MDT), including agreement of a Consultant Neuro-Radiologist that imaging changes are most in keeping with recurrence and not pseudo-progression and patient is planned for systemic treatment. Patients with a prior recurrence treated by surgical resection alone are eligible at time of first recurrence planned for systemic treatment. 3. Patients must have received initial first-line treatment with standard dose conventionally fractionated radiotherapy (i.e. 54-60 Gy in 28-33 fractions) with concomitant and adjuvant temozolomide (TMZ) (STUPP regime) 3.1 Minimum of 3 cycles of adjuvant TMZ must have been received 3.2. Minimum of SD (or PR/CR) at the end of first-line treatment 4. ≥4 months since day 28 of the last cycle of TMZ 5. Karnofsky Performance Status ≥60 6. Adequate hematologic, renal, and hepatic function within 14 days prior to randomisation: 6.1. Absolute neutrophil count (ANC) ≥1.5 x 109/L 6.2. Platelet count ≥100 x 109/L 6.3. Serum creatinine clearance (measured or eGFR) >30ml/min 6.4. Total serum bilirubin ≤1.5 x upper limit of normal (ULN) 6.5. Liver transaminases <2.5 x ULN 7. If surgery has been performed for first recurrence then the wound must be adequately healed and there must be residual enhancing disease on MRI within 21 days of surgery or new enhancement at later follow up deemed suitable for systemic treatment 8. Recovered from previous treatment side-effects ≤ Grade 2 9. If on systemic steroids, must be on stable (≥7 days) or decreasing dose of steroids 10. Willing and able to provide trial-specific informed consent 11. Willing and able to comply with trial requirements 12. Aged 16 years old and over 13. Able to start treatment within 28 days of randomisation |
| Participant exclusion criteria | Current exclusion criteria as of 08/11/2022: 1. Pathology inconsistent with IDH WT glioblastoma multiforme (GBM) (e.g. patients with molecular features of PXA or BRAF mutation (on original pathology) will be excluded) 2. Prior invasive malignancy (except non-melanoma skin cancer), unless disease free for a minimum of one year 3. Prior treatment with stereotactic radiotherapy, brachytherapy or Convection Enhanced Delivery (CED) of any agent 4. Prior treatment, apart from debulking surgery, for first recurrence of GBM 5. Any active co-morbidity making patient unsuitable for trial treatment in the view of the Investigator 6. Personal history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric diagnosis other than depression associated with their underlying glioma condition 7. Prior allergic reaction or significant toxicity (≥Grade 3 CTCAE) related to temozolomide treatment 8. Current or recent cannabis or cannabinoid-based medications within 30 days of randomisation and/or unwilling to abstain for the duration of the trial 9. Women who are pregnant, breastfeeding or a woman of childbearing potential who is unwilling to use effective contraceptive methods during trial treatment and for 6 months after completion of trial treatment 9.1. Women of childbearing age must have a negative pregnancy test within 7 days prior to randomisation 10. Men who are sexually active and unwilling/unable to use medically acceptable forms of contraception during trial treatment or for 6 months after completion of trial treatment 11. Contra-indication to MRI or gadolinium 12. Hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 13. Known hypersensitivity to cannabinoids or excipients of the IMP 14. Known history of current or prior alcohol or drug dependence 15. Known Hepatitis B (HBV), Cytomegalovirus (CMV) or opportunistic infection 16. Has received a live vaccine within 28 days prior to randomisation 17. Unable to administer oromucosal medication due to mucosal lesions or other issues 18. Participation in another therapeutic clinical trial whilst taking part in this trial 19. Any psychological, familial, sociological or geographical condition hampering protocol compliance _____ Previous exclusion criteria: 1. Pathology inconsistent with IDH WT glioblastoma multiforme (GBM) (e.g. patients with molecular features of PXA or BRAF mutation (on original pathology) will be excluded) 2. Prior invasive malignancy (except non-melanoma skin cancer), unless disease free for a minimum of one year 3. Prior treatment with stereotactic radiotherapy, brachytherapy or Convection Enhanced Delivery (CED) of any agent 4. Prior treatment, apart from debulking surgery, for first recurrence of GBM 5. Any active co-morbidity making patient unsuitable for trial treatment in the view of the Investigator 6. Personal history of schizophrenia, other psychotic illness, severe personality disorder or other significant psychiatric diagnosis other than depression associated with their underlying glioma condition 7. Prior allergic reaction or significant toxicity (≥Grade 3 CTCAE) related to temozolomide treatment 8. Current or recent cannabis or cannabinoid-based medications within 30 days of randomisation and/or unwilling to abstain for the duration of the trial 9. Women who are pregnant, breastfeeding or a woman of childbearing potential who is unwilling to use effective contraceptive methods during trial treatment and for 6 months after completion of trial treatment 9.1. Women of childbearing age must have a negative pregnancy test within 7 days prior to randomisation 10. Men who are sexually active and unwilling/unable to use medically acceptable forms of contraception during trial treatment or for 6 months after completion of trial treatment 11. Contra-indication to MRI or gadolinium 12. Hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption 13. Known hypersensitivity to cannabinoids or excipients of the IMP 14. Known history of current or prior alcohol or drug dependence 15. Unable to administer oromucosal medication due to mucosal lesions or other issues 16. Participation in another therapeutic clinical trial whilst taking part in this trial 17. Any psychological, familial, sociological or geographical condition hampering protocol compliance |
| Recruitment start date | 03/02/2023 |
| Recruitment end date | 31/10/2023 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Cambridge
CB2 0QQ
United Kingdom
Glasgow
G12 0YN
United Kingdom
Bristol
BS2 8ED
United Kingdom
London
W6 8RF
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Wirral
CH63 4JY
United Kingdom
London
SE1 9RT
United Kingdom
Edgbaston
Birmingham
B15 2TH
United Kingdom
Leeds
LS9 7TF
United Kingdom
Withington
Manchester
M20 4BX
United Kingdom
Cardiff
CF14 2TL
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Northwood
HA6 2RN
United Kingdom
Cottingham
Hull
HU16 5JQ
United Kingdom
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Sponsor information
University/education
Research Support Group
Aston Webb Building (B Block)
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 415 8011 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
| Website | http://www.birmingham.ac.uk/index.aspx |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- The Brain Tumour Charity
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/02/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on a website Applications to access the data collected within the ARISTOCRAT trial will be subject to the CRCTU's data-sharing application process. |
| IPD sharing plan | Scientifically sound proposals from appropriately qualified researchers will be considered for data sharing. Requests should be made by returning a Data Sharing Request Form to newbusiness@trials.bham.ac.uk; this captures the research requirements, statistical analysis plan, and intended publication schedule. Requests will be reviewed by the Cancer Research UK Clinical Trials Unit (CRCTU) Directors in discussion with the Chief Investigator (CI), Trial Management Group (TMG) and independent Trial Steering Committee (SAB). They will consider the scientific validity of the request, qualifications of the researchers, CI, TMG & TSC views, consent arrangements, practicality of anonymizing the requested data & contractual obligations. If supportive of the request, and where not already obtained, Sponsor consent for data transfer will be sought before notifying applicants of the outcome. It is anticipated that applicants will be notified within 3 months of receipt of the original request. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 15/01/2024 | 16/01/2024 | Yes | No |
Editorial Notes
16/08/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 03/08/2024 to 31/10/2023.
2. The overall end date was changed from 01/08/2025 to 01/02/2026.
3. The intention to publish date was changed from 01/08/2026 to 01/02/2027.
4. The plain English summary was updated to reflect these changes.
22/02/2024: The study participating centres Western General Hospital, Edinburgh and Southampton General Hospital were removed and Aberdeen Royal Infirmary was added.
16/01/2024: The following changes were made to the trial record:
1. Publication reference added.
2. The study participating centre Belfast City Hospital was removed.
31/08/2023: The following changes were made to the study record:
1. Ethics approval details and inclusion criteria updated.
2. The study participating centres were updated to remove and add Churchill Hospital, Mount Vernon Cancer Centre, Castle Hill Hospital, and Derriford Hospital.
16/05/2023: Lower age limit added, Wales added to countries of recruitment.
17/02/2023: Cancer Research UK plain English summary link added to plain English summary field.
07/02/2023: The following changes were made to the trial record:
1. The recruitment start date was changed from 31/12/2022 to 03/02/2023.
2. The recruitment end date was changed from 01/05/2024 to 03/08/2024.
06/12/2022: The recruitment start date was changed from 01/12/2022 to 31/12/2022.
08/11/2022: The following changes were made to the trial record:
1. The ethics approval was added.
2. The exclusion criteria were changed.
3. The recruitment start date was changed from 01/11/2022 to 01/12/2022.
4. The participant level data sharing statement was added.
01/11/2022: Internal review.
25/10/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 25/10/2022
22/09/2022: Trial's existence confirmed by the HRA.
